Panitumumab

THOUSAND OAKS, Calif., Feb. 3, 2026 /PRNewswire/ -- Amgen (NASDAQ: AMGN) today announced financial results for the fourth quarter and full year of 2025 versus the comparable periods in 2024. "Amgen delivered strong performance in 2025, with double-digit growth in revenues and earnings per share. We enter 2026 with momentum across a broad portfolio of medicines and a clear path towards advancing innovative therapies to deliver sustained long-term growth," said Robert A. Bradway, chairman and chief executive officer. Key results include: For the fourth quarter, total revenues increased 9% to $9.9 billion in comparison to the fourth quarter of 2024. Product sales grew 7%, driven by 10% volume growth, partially offset by 4% lower net selling price. For the full year, total revenues increased 10% to $36.8 billion in comparison to the full year of 2024. Product sales grew 10%, driven by 13% volume growth, partially offset by 3% lower net selling price. Eighteen products achieved record sales for the full year. Fourteen products exceeded one billion dollars in annual sales. Thirteen products delivered at least double-digit sales growth for the full year. GAAP earnings per share (EPS) increased 111% from $1.16 to $2.45 for the fourth quarter, driven by higher revenues and lower net unrealized losses on equity investments, partially offset by higher operating expenses. For the full year, GAAP EPS increased 88% from $7.56 to $14.23, driven by higher revenues and net unrealized gains on our BeOne Medicines Ltd. (BeOne) equity investment, partially offset by higher operating expenses, including Otezla® (apremilast) intangible asset impairment charges of $1.2 billion recorded in 2025, following the selection of Otezla® for Medicare price setting, as part of the Inflation Reduction Act (IRA). For the fourth quarter, GAAP operating income increased from $2.3 billion to $2.7 billion, and GAAP operating margin increased 2.5 percentage points to 29.0%. For the full year, GAAP operating income increased from $7.3 billion to $9.1 billion, and GAAP operating margin increased 3.1 percentage points to 25.8%. Non-GAAP EPS remained relatively unchanged from $5.31 to $5.29 for the fourth quarter as higher operating expenses were partially offset by higher revenues. For the full year, non-GAAP EPS increased 10% from $19.84 to $21.84, driven by higher revenues, partially offset by higher operating expenses. For the fourth quarter, non-GAAP operating income remained relatively unchanged at $4.0 billion, and non-GAAP operating margin decreased 3.5 percentage points to 42.8%. For the full year, non-GAAP operating income increased from $15.0 billion to $16.2 billion, and non-GAAP operating margin decreased 0.8 percentage points to 46.1%. The Company generated $8.1 billion of free cash flow for the full year of 2025 versus $10.4 billion for the full year of 2024, driven by timing of working capital, primarily collections and higher capital expenditures, partially offset by business performance and lower interest payments. References in this release to "non-GAAP" measures, measures presented "on a non-GAAP basis," "free cash flow" (computed by subtracting capital expenditures from operating cash flow), "EBITDA, or earnings before interest, taxes, depreciation and amortization" (computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income) and "debt leverage ratio" (calculated as the ratio of GAAP total debt to EBITDA) refer to non-GAAP financial measures. Adjustments to the most directly comparable GAAP financial measures and other items are presented on the attached reconciliations. Refer to Non-GAAP Financial Measures below for further discussion. Product Sales Performance General Medicine Repatha® (evolocumab) sales increased 44% year-over-year to $870 million in the fourth quarter, driven by 31% volume growth, 8% higher net selling price, and higher inventory levels. Sales increased 36% for the full year, driven by volume growth. For 2026, we expect net selling price to decline by roughly mid-single-digits. EVENITY® (romosozumab-aqqg) sales increased 39% year-over-year to $599 million in the fourth quarter and 34% for the full year, primarily driven by volume growth. Prolia® (denosumab) sales decreased 10% year-over-year to $1.1 billion in the fourth quarter, driven by 8% lower net selling price and decreased volume. Sales increased 1% for the full year, primarily driven by 2% volume growth and 2% favorable changes to estimated sales deductions, partially offset by lower net selling price. For 2026, we expect accelerated sales erosion driven by increased competition, as multiple biosimilars have launched globally. Rare Disease TEPEZZA® (teprotumumab-trbw) sales decreased 1% year-over-year to $457 million in the fourth quarter, primarily driven by 13% lower inventory levels and unfavorable changes to estimated sales deductions, partially offset by 11% volume growth and higher net selling price. Sales increased 3% for the full year, primarily driven by higher net selling price. KRYSTEXXA® (pegloticase) sales increased 26% year-over-year to $435 million in the fourth quarter, driven by higher inventory levels, higher net selling price, and volume growth. Sales increased 13% for the full year, driven by volume growth and higher net selling price. UPLIZNA® (inebilizumab-cdon) sales increased 131% year-over-year to $233 million in the fourth quarter and 73% for the full year, primarily driven by volume growth. TAVNEOS® (avacopan) sales increased 88% year-over-year to $152 million in the fourth quarter, primarily driven by 69% volume growth and 18% higher inventory levels. Sales increased 62% for the full year, driven by volume growth, partially offset by lower net selling price. Ultra-Rare products generated $157 million of sales in the fourth quarter. Sales decreased 27% year-over-year for the fourth quarter and 5% for the full year, primarily driven by generic competition for RAVICTI. For 2026, we expect continued RAVICTI sales erosion driven by generic competition. Inflammation TEZSPIRE® (tezepelumab-ekko) sales increased 60% year-over-year to $474 million in the fourth quarter, primarily driven by 51% volume growth, and to a lesser degree, higher inventory levels and favorable changes to estimated sales deductions. Sales increased 52% for the full year, driven by volume growth. Otezla® (apremilast) sales were flat year-over-year at $625 million in the fourth quarter. Sales increased 7% for the full year, primarily driven by 3% volume growth and 2% favorable changes to estimated sales deductions. Enbrel® (etanercept) sales decreased 48% year-over-year to $532 million in the fourth quarter, primarily driven by 35% lower net selling price resulting from the impact of the U.S. Medicare Part D redesign and increased 340B Program mix, and 17% unfavorable changes to estimated sales deductions. Sales decreased 33% for the full year, primarily driven by 36% lower net selling price resulting from increased 340B Program mix, the impact of the U.S. Medicare Part D redesign and higher commercial discounts, partially offset by 4% higher volume. We expect Enbrel and Otezla, and to a lesser extent KRYSTEXXA, TEZSPIRE and Repatha, to follow the historical pattern of lower sales in the first quarter relative to subsequent quarters, in part due to the impact of benefit plan changes, insurance reverification and increased co-pay expenses as U.S. patients work through deductibles. AMJEVITA® (adalimumab-atto)/AMGEVITA™ (adalimumab) sales decreased 41% year-over-year to $174 million in the fourth quarter, primarily driven by lower volume. Sales decreased 22% for the full year, driven by lower volume and lower net selling price. PAVBLU® (aflibercept-ayyh) generated $258 million of sales in the fourth quarter and $700 million for the full year. Sales increased 21% quarter-over-quarter, primarily driven by volume growth. WEZLANA® (ustekinumab-auub)/WEZENLA™ (ustekinumab) generated $44 million of sales in the fourth quarter and $273 million for the full year. Oncology BLINCYTO® (blinatumomab) sales increased 8% year-over-year to $413 million in the fourth quarter, driven by 5% higher inventory levels and higher net selling price. Sales increased 28% for the full year, driven by volume growth. Vectibix® (panitumumab) sales increased 30% year-over-year to $319 million in the fourth quarter, driven by 23% volume growth, and to a lesser degree, higher net selling price and higher inventory levels. Sales increased 12% for the full year, primarily driven by volume growth. KYPROLIS® (carfilzomib) sales decreased 6% year-over-year to $351 million in the fourth quarter and 6% for the full year, primarily driven by lower volume. LUMAKRAS®/LUMYKRAS™ (sotorasib) sales increased 8% year-over-year to $92 million in the fourth quarter, primarily driven by 22% volume growth, partially offset by 9% lower net selling price and 6% lower inventory levels. Sales increased 4% for the full year, driven by 13% volume growth, partially offset by lower net selling price. XGEVA® (denosumab) sales decreased 20% year-over-year to $447 million in the fourth quarter and 6% for the full year, primarily driven by lower volume. For 2026, we expect accelerated sales erosion driven by increased competition, as multiple biosimilars have launched globally. Nplate® (romiplostim) sales increased 14% year-over-year to $385 million in the fourth quarter, primarily driven by 9% volume growth and 4% higher inventory levels. Sales increased 5% for the full year, driven by volume growth. U.S. government orders were $90 million in 2025 compared to $128 million in 2024. Excluding these U.S. government orders, Nplate sales increased 8% for the full year, driven by volume growth. IMDELLTRA® (tarlatamab-dlle)/IMDYLLTRA™ (tarlatamab) generated $234 million of sales in the fourth quarter and $627 million for the full year. Sales increased 31% quarter-over-quarter, driven by volume growth. MVASI® (bevacizumab-awwb) sales increased 9% year-over-year to $188 million in the fourth quarter, primarily driven by 15% favorable changes to estimated sales deductions, and to a lesser degree, higher net selling price and higher inventory levels, partially offset by lower volume. Sales increased 6% for the full year, driven by favorable changes to estimated sales deductions and higher net selling price, partially offset by lower volume. Established Products Our established products, which consist of Aranesp® (darbepoetin alfa), Parsabiv® (etelcalcetide), and Neulasta® (pegfilgrastim), generated $554 million of sales in the fourth quarter. Sales increased 15% year-over-year for the fourth quarter, driven by higher net selling price and favorable changes to estimated sales deductions. Sales increased 2% for the full year, driven by 7% favorable changes to estimated sales deductions, partially offset by lower net selling price. Product Sales Detail by Product and Geographic Region Operating Expense, Operating Margin and Tax Rate Analysis On a GAAP basis: Total Operating Expenses increased 5% year-over-year for the fourth quarter and increased 6% for the full year. Cost of Sales as a percentage of product sales decreased 3.9 percentage points for the fourth quarter and decreased 5.9 percentage points for the full year, driven by lower amortization expense from acquisition-related assets, including Horizon-acquired inventory, and lower manufacturing costs, partially offset by higher profit share expense and changes in our sales mix. Research & Development (R&D) expenses increased 24% for the fourth quarter primarily driven by higher spend in the later-stage clinical programs, including MariTide, and in the research and early pipeline, including business development activities in the fourth quarter of 2025. R&D expenses increased 22% for the full year driven by higher spend in the later-stage clinical programs, including MariTide, and in the research and early pipeline, partially offset by lower spend in marketed product support. This increase includes the impact of business development activities in 2025. Selling, General & Administrative (SG&A) expenses increased 4% for the fourth quarter driven by higher commercial product-related expenses, partially offset by lower Horizon acquisition-related expenses and lower general and administrative expenses. SG&A expenses decreased 1% for the full year driven by lower Horizon acquisition-related expenses and lower amortization expense from acquisition-related assets, partially offset by higher general and administrative expenses, including technology-related spend. Other operating expenses for the full year included Otezla® intangible asset impairment charges of $1.2 billion, following the selection of Otezla® for Medicare price setting, as part of the Inflation Reduction Act (IRA). Operating Margin as a percentage of product sales increased 2.5 percentage points to 29.0% for the fourth quarter and increased 3.1 percentage points to 25.8% for the full year. Tax Rate decreased 7.8 percentage points for the fourth quarter and increased 2.8 percentage points for the full year. The fourth quarter tax rate decrease was due to the prior-year deferred tax adjustments associated with the U.S. tax on the earnings of our foreign subsidiaries, partially offset by the change in earnings mix, including lower amortization expense from the fair value step-up of inventory acquired from Horizon as compared to the prior year. The full year tax rate increase was due to the change in earnings mix, including the net unrealized gains on our equity investments compared to net unrealized losses on equity investments in the prior year, partially offset by the prior-year deferred tax adjustments associated with U.S. tax on the earnings of our foreign subsidiaries and the current year Otezla® intangible asset impairment charges and related tax impacts. On a non-GAAP basis: Total Operating Expenses increased 16% year-over-year for the fourth quarter and increased 12% for the full year. Cost of Sales as a percentage of product sales increased 1.5 percentage points for the fourth quarter and increased 0.4 percentage points for the full year, driven by higher profit share expense and changes in our sales mix, partially offset by lower manufacturing costs. R&D expenses increased 26% for the fourth quarter driven by higher spend in the later-stage clinical programs, including MariTide, and in the research and early pipeline, including business development activities in the fourth quarter of 2025. R&D expenses increased 22% for the full year driven by higher spend in the later-stage clinical programs, including MariTide, and in the research and early pipeline, partially offset by lower spend in marketed product support. This increase includes the impact of business development activities in 2025. SG&A expenses increased 6% for the fourth quarter driven by higher commercial product-related expenses, partially offset by lower general and administrative expenses. SG&A expenses increased 2% for the full year driven by higher general and administrative expenses, including technology-related spend. Operating Margin as a percentage of product sales decreased 3.5 percentage points for the fourth quarter to 42.8% and decreased 0.8 percentage points to 46.1% for the full year. Tax Rate increased 1.6 percentage points for the fourth quarter and increased 1.4 percentage points for the full year. The fourth quarter tax rate increase was primarily due to prior year net favorable items as compared to the current year. The full year tax rate increase was due to the change in earnings mix and prior year net favorable items as compared to the current year. Cash Flow and Balance Sheet The Company generated $1.0 billion of free cash flow in the fourth quarter of 2025 versus $4.4 billion in the fourth quarter of 2024, driven by timing of working capital, primarily collections, timing of tax payments and higher capital expenditures, partially offset by business performance. The Company generated $8.1 billion of free cash flow for the full year of 2025 versus $10.4 billion in 2024. The Company declared a fourth quarter 2025 dividend on October 31, 2025 of $2.38 per share that was paid on December 12, 2025 to all stockholders of record as of November 21, 2025, representing a 6% increase from the same period in 2024. The Company retired $6.0 billion of debt for the full year of 2025. During the fourth quarter and full year of 2025, there were no repurchases of shares of common stock under our stock repurchase program. Cash and cash equivalents totaled $9.1 billion and debt outstanding totaled $54.6 billion as of December 31, 2025. Debt leverage was approximately 3.2 times EBITDA as of December 31, 2025. 2026 Guidance For the full year 2026, the Company expects: Total revenues in the range of $37.0 billion to $38.4 billion. On a GAAP basis, EPS in the range of $15.45 to $16.94, and a tax rate in the range of 15.5% to 17.0%. On a non-GAAP basis, EPS in the range of $21.60 to $23.00, and a tax rate in the range of 16.0% to 17.5%. Capital expenditures to be approximately $2.6 billion. Share repurchases not to exceed $3 billion. Fourth Quarter Product and Pipeline Update The Company provided the following updates on selected product and pipeline programs: General Medicine MariTide (maridebart cafraglutide, AMG 133) MariTide is a differentiated antibody-peptide conjugate that activates the glucagon like peptide 1 (GLP-1) receptor and antagonizes the glucose-dependent insulinotropic polypeptide receptor (GIPR). MARITIME-1, a Phase 3 study of MariTide for chronic weight management, is ongoing in adults living with obesity or overweight, without Type 2 diabetes (T2D). MARITIME-2, a Phase 3 study of MariTide for chronic weight management, is ongoing in adults living with obesity or overweight, with T2D. MARITIME-CV, a Phase 3 study of MariTide on cardiovascular (CV) outcomes, is enrolling adults living with established atherosclerotic cardiovascular disease and obesity or overweight. MARITIME-HF, a Phase 3 study of MariTide on reduction of heart failure events and cardiovascular risk, is enrolling adults living with heart failure with preserved or mildly reduced ejection fraction and obesity. MARITIME-OSA-1, a Phase 3 study of MariTide, is enrolling adults living with obstructive sleep apnea on positive airway pressure therapy and living with obesity or overweight. MARITIME-OSA-2, a Phase 3 study of MariTide, is enrolling adults living with obstructive sleep apnea not on positive airway pressure therapy and living with obesity or overweight. Part 2 of the Phase 2 chronic weight management study, an exploratory evaluation of MariTide treatment for an additional 52 weeks in people who lost at least 15% of their body weight in the 52-week Part 1 of the Phase 2 chronic weight management study is complete. Key findings include: The large majority of participants maintained the weight loss achieved in Part 1 for an additional 52 weeks on a lower monthly dose or quarterly dose of MariTide. The second year of MariTide treatment was very well tolerated, including at quarterly doses, with a very low incidence of nausea and vomiting and no new safety signals observed. Improvements in cardiometabolic parameters were sustained with MariTide at effective maintenance doses for a full second year. A Phase 2 study of MariTide for the treatment of T2D in adults living with and without obesity has completed the 24-week timepoint. Key findings include: Robust and clinically meaningful reduction in both hemoglobin A1c (HbA1c) and weight with monthly MariTide at 24 weeks. In line with results seen in the T2D population in Part 1 of the Phase 2 chronic weight management study, at 24 weeks. Safety and tolerability profile consistent with the GLP-1 class. The most common side effects were gastrointestinal-related, predominantly mild-to-moderate in nature, and occurred primarily during dose escalation. Favorable improvement in cardiometabolic parameters. The Company expects to initiate Phase 3 studies of MariTide in people living with T2D in 2026. AMG 513 A Phase 1 study of AMG 513 is enrolling adults living with obesity. Repatha In November 2025, results from the landmark Phase 3 VESALIUS-CV clinical trial of more than 12,000 patients with atherosclerosis or diabetes without a prior heart attack or stroke were presented at the American Heart Association Scientific Sessions and simultaneously published in the New England Journal of Medicine. In this study, Repatha: Demonstrated a 25% relative reduction in the risk of a composite of coronary heart disease death, heart attack or ischemic stroke (3-P MACE). Demonstrated a 19% reduction in a broader composite that also included any ischemia-driven arterial revascularization (4-P MACE). Reduced the risk of heart attack by 36%. Further analysis from VESALIUS-CV will be presented on the subgroup of patients without significant atherosclerosis at the upcoming American College of Cardiology in March 2026. EVOLVE-MI, a Phase 4 study of Repatha initiated within 10 days of an acute myocardial infarction to reduce the risk of CV events, is ongoing. Olpasiran (AMG 890) Olpasiran is a potentially best-in-class small interfering ribonucleic acid (siRNA) molecule that reduces lipoprotein(a) (Lp(a)) synthesis in the liver. The OCEAN(a)-Outcomes trial, a Phase 3 secondary prevention CV outcomes study, is ongoing in patients with atherosclerotic CV disease and elevated Lp(a). The OCEAN(a)-PreEvent trial, a Phase 3 primary prevention CV outcomes study is enrolling patients with elevated Lp(a) at risk for a first major CV event. Rare Disease UPLIZNA In November, the European Commission approved UPLIZNA for the treatment of adults with active immunoglobulin G4-related disease (IgG4-RD). In December, the U.S. Food and Drug Administration (FDA) approved UPLIZNA for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) and anti-muscle specific tyrosine kinase (MuSK) antibody positive. The Company expects to initiate Phase 3 studies of UPLIZNA in patients with autoimmune hepatitis and in patients with chronic inflammatory demyelinating polyneuropathy in 2026. TEPEZZA A Phase 3 study of TEPEZZA in Japan is ongoing in patients with chronic/low clinical activity score thyroid eye disease (TED). A Phase 3 study evaluating the subcutaneous route of administration of teprotumumab is ongoing in patients with TED. Study completion is expected in H2 2026. TAVNEOS TAVNEOS (avacopan) was approved by the FDA in October 2021 for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) in combination with standard therapy including glucocorticoids. TAVNEOS was developed by ChemoCentryx, Inc. Amgen acquired ChemoCentryx in October 2022, after TAVNEOS had been on the market for a year. On January 16, 2026, the U.S. Food and Drug Administration (FDA) requested that ChemoCentryx voluntarily withdraw TAVNEOS from the U.S. market. The FDA raised concerns about the process followed by ChemoCentryx to re-adjudicate primary endpoint results for 9 of the 331 patients in its pivotal clinical trial. Hepatotoxicity, which is a known infrequent risk of TAVNEOS treatment for AAV, was also raised in the context of the benefit-risk profile of the medicine. Amgen is not aware of any issue with the underlying patient data from the ChemoCentryx clinical trial. And after review of the relevant clinical data and years of real-world evidence, Amgen is confident that TAVNEOS demonstrates effectiveness and a favorable benefit–risk profile. On January 28, 2026, following FDA regulatory process, Amgen informed the Agency that it did not intend to withdraw TAVNEOS from the market. Amgen is evaluating next steps with the FDA to determine a path forward, while keeping patient safety, needs and support at the forefront. A Phase 3, open-label study of TAVNEOS in combination with rituximab or a cyclophosphamide-containing regimen is enrolling patients from 6 years to < 18 years of age with active ANCA-associated vasculitis (Granulomatosis with Polyangiitis (GPA)/Microscopic Polyangiitis (MPA)). Dazodalibep Dazodalibep is a fusion protein that inhibits CD40L. Two Phase 3 studies of dazodalibep in Sjögren's disease are underway. The first study is ongoing in patients with moderate-to-severe systemic disease activity. The second study has completed enrollment of patients with moderate to high symptom burden with low systemic disease activity. Completion of both studies is expected in H2 2026. Daxdilimab Daxdilimab is a first-in-class plasmacytoid dendritic cell (pDC) depleting monoclonal antibody targeting immunoglobulin-like transcript 7 (ILT7). A Phase 2 study of daxdilimab in adult patients with moderate-to-severe primary discoid lupus erythematosus (DLE) is complete. The study met the primary endpoint of mean change in the Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) score from baseline to week 24, demonstrating statistically significant improvements in disease activity with both doses tested. The study met the key secondary endpoint of clinical response by CLASI-A 50 and by the Cutaneous Lupus Activity Investigator's Global Assessment CLA-IGA 0/1, at week 24 with both doses tested. Daxdilimab showed an acceptable safety and tolerability profile. A Phase 2 study of daxdilimab in 12 patients with dermatomyositis (DM) and antisynthetase inflammatory myositis (ASIM) is complete. Total Improvement Score (TIS) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) showed positive trends, but the sample size was too limited to assess efficacy. Daxdilimab showed an acceptable safety and tolerability profile. AMG 329 AMG 329 is a fully human monoclonal antibody targeting FMS-like tyrosine kinase 3 (FLT3) ligand. A Phase 2 study of AMG 329 is ongoing in patients with Sjögren's disease. AMG 732 AMG 732 is an insulin-like growth factor-1 receptor (IGF-1R) targeting monoclonal antibody. A Phase 2 study of AMG 732 is enrolling patients with moderate-to-severe active TED. Inflammation TEZSPIRE Two Phase 3 studies of TEZSPIRE are enrolling adults with moderate to very severe chronic obstructive pulmonary disease (COPD) and a BEC ≥ 150 cells/µl. A Phase 3 study of TEZSPIRE is ongoing in patients with eosinophilic esophagitis. Study completion is expected in H2 2026. Rocatinlimab (AMG 451/KHK4083) Rocatinlimab is a first-in-class T-cell rebalancing monoclonal antibody that inhibits and reduces OX40-positive pathogenic T-cells. As part of ongoing portfolio prioritization, the Company will terminate the rocatinlimab development and commercialization collaboration with Kyowa Kirin, subject to Hart-Scott-Rodino review. Kyowa Kirin will assume ownership of and responsibility for the program. The Company will provide certain transition services to Kyowa Kirin. Blinatumomab Blinatumomab is a bispecific T-cell engager (BiTE®) molecule targeting CD19. A Phase 2 study of blinatumomab in autoimmune disease is enrolling adults with systemic lupus erythematosus (SLE), with and without nephritis, and is enrolling adults with refractory rheumatoid arthritis. Inebilizumab Inebilizumab is a B-cell depleting monoclonal antibody targeting CD19. A Phase 2 study of inebilizumab in autoimmune disease is enrolling adults with SLE with nephritis. AMG 104 (AZD8630) AMG 104 is an inhaled anti-thymic stromal lymphopoietin (TSLP) fragment antigen-binding (Fab) protein. A Phase 2 study is ongoing in patients with asthma. Study completion is expected in H1 2026. Oncology BLINCYTO / blinatumomab A potentially registration-enabling Phase 2 study of subcutaneous blinatumomab is enrolling both adults and adolescents with relapsed or refractory CD19-positive Philadelphia chromosome (Ph) negative B-cell precursor acute lymphoblastic leukemia (B-ALL). Golden Gate, a Phase 3 study of BLINCYTO alternating with low-intensity chemotherapy, is enrolling older adult patients with newly diagnosed CD19-positive Ph-negative B-ALL. A Phase 1b/2 study of subcutaneous blinatumomab was initiated and is enrolling pediatric patients with relapsed / refractory and minimal residual disease positive (MRD+) B-ALL. IMDELLTRA / tarlatamab IMDELLTRA is the first and only FDA-approved delta-like ligand 3 (DLL3) targeting BiTE molecule. In November, the FDA granted full approval to IMDELLTRA for the treatment of adult patients with extensive stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Additional Regulatory reviews are underway in multiple additional geographies including the European Union, China, and Japan. The Company is advancing a comprehensive, global clinical development program across extensive-stage (ES) and limited-stage (LS) SCLC: DeLLphi-303, a Phase 1b study of IMDELLTRA in combination with a programmed cell death protein ligand-1 (PD-L1) inhibitor, carboplatin and etoposide or separately in combination with a PD-L1 inhibitor alone, is ongoing in patients with first-line ES-SCLC. DeLLphi-305, a Phase 3 study of IMDELLTRA and durvalumab is ongoing in first-line ES-SCLC in the maintenance setting. DeLLphi-306, a Phase 3 study of IMDELLTRA following concurrent chemoradiation therapy, is enrolling patients with LS-SCLC. DeLLphi-308, a Phase 1b study evaluating subcutaneous tarlatamab, is enrolling patients with second line or later ES-SCLC. DeLLphi-309, a Phase 2 study evaluating alternative intravenous dosing regimens of IMDELLTRA in second-line ES-SCLC, is enrolling patients. DeLLphi-310, a Phase 1b study of IMDELLTRA in combination with YL201, a B7-H3 targeting antibody-drug conjugate, with or without a PD-L1 inhibitor, is enrolling patients with ES-SCLC. DeLLphi-311, a Phase 1b study of IMDELLTRA in combination with etakafusp alfa (AB248), a novel CD8+ T-cell selective interleukin-2 (IL-2), is enrolling patients with second-line or later ES-SCLC. DeLLphi-312, a Phase 3 study of IMDELLTRA in combination with carboplatin, etoposide and durvalumab, is enrolling patients with first-line ES-SCLC. Xaluritamig (AMG 509) Xaluritamig is a first-in-class bispecific T-cell engager targeting six-transmembrane epithelial antigen of prostate 1 (STEAP1). XALute, a Phase 3 study of xaluritamig, is enrolling patients with metastatic castrate resistant prostate cancer (mCRPC) who have previously been treated with taxane-based chemotherapy. XALience, a Phase 3 study of xaluritamig in combination with abiraterone versus investigator's choice therapy is enrolling patients with chemotherapy-naïve mCRPC. A Phase 1 study of xaluritamig monotherapy and xaluritamig in combination with abiraterone is ongoing in patients with mCRPC who have not yet received taxane-based chemotherapy. This study is also ongoing in patients with mCRPC who have previously received taxane-based chemotherapy in a fully outpatient treatment setting to further improve administration convenience. A Phase 1b study of neoadjuvant xaluritamig therapy prior to radical prostatectomy is enrolling patients with newly diagnosed localized intermediate or high‐risk prostate cancer. A Phase 1b study of xaluritamig is ongoing with high-risk biochemically recurrent prostate cancer after definitive therapy. A Phase 1b study of xaluritamig in combination with androgen receptor pathway inhibitors is enrolling patients with metastatic hormone-sensitive prostate cancer. A Phase 1b study of xaluritamig was initiated in adult, adolescent and pediatric patients with relapsed or refractory Ewing sarcoma. Bemarituzumab Bemarituzumab is a first-in-class fibroblast growth factor receptor 2b (FGFR2b) targeting monoclonal antibody. Based upon data from the FORTITUDE-101 and FORTITUDE-102 Phase 3 studies, the Company does not intend to pursue regulatory approval in first-line gastric cancer. FORTITUDE-103, a Phase 1b/2 study of bemarituzumab plus oral chemotherapy regimens with or without nivolumab in patients with first-line gastric cancer was stopped. FORTITUDE-301, a Phase 1b/2 basket study of bemarituzumab monotherapy in patients with solid tumors with FGFR2b overexpression was completed. AMG 193 AMG 193 is a first-in-class small molecule methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor. A Phase 2 study of AMG 193 is ongoing patients with methylthioadenosine phosphorylase (MTAP)-null previously treated advanced non-small cell lung cancer (NSCLC). A Phase 1/1b/2 study of AMG 193 has completed enrollment of patients with advanced MTAP-null solid tumors in the dose-expansion portion of the study. A Phase 1b study of AMG 193 alone or in combination with other therapies is enrolling patients with advanced MTAP-null thoracic malignancies. A Phase 1b study of AMG 193 in combination with other therapies is enrolling patients with advanced MTAP-null gastrointestinal, biliary tract or pancreatic cancers. LUMAKRAS/LUMYKRAS CodeBreaK 301, a Phase 3 study of LUMAKRAS in combination with Vectibix and FOLFIRI vs. FOLFIRI with or without bevacizumab-awwb, is enrolling patients with first-line KRAS G12C–mutated metastatic colorectal cancer. CodeBreaK 202, a Phase 3 study of LUMAKRAS plus platinum doublet chemotherapy vs. pembrolizumab plus chemotherapy, is enrolling patients with first-line KRAS G12C–mutated and PD-L1 negative advanced NSCLC. Nplate PROCLAIM, a Phase 3 study of Nplate for the treatment of chemotherapy-induced thrombocytopenia, is ongoing in patients with NSCLC, ovarian cancer or breast cancer. Biosimilars A randomized, double-blind comparative clinical study of ABP 206 compared with OPDIVO® has completed enrollment in patients with treatment-naïve unresectable or metastatic melanoma. A randomized, double-blind pharmacokinetic similarity study of ABP 234 compared with KEYTRUDA® (pembrolizumab) is enrolling patients with early-stage non-squamous NSCLC as adjuvant treatment. A randomized, double-blind combined pharmacokinetic/comparative clinical study of ABP 234 compared to KEYTRUDA has completed enrollment patients with advanced or metastatic non-squamous NSCLC. A randomized, double-blind, pharmacokinetic similarity/comparative clinical study of ABP 692 compared to OCREVUS® (ocrelizumab) is enrolling patients with relapsing-remitting multiple sclerosis. TEZSPIRE is being developed in collaboration with AstraZeneca. AMG 104 is being developed in collaboration with AstraZeneca. Xaluritamig, formerly AMG 509, is being developed pursuant to a research collaboration with Xencor, Inc. YL201 is an investigational B7-H3 targeting antibody-drug conjugate being developed by MediLink. Etakafusp alfa (AB248) is a novel CD8+ T cell selective interleukin-2 (IL-2) being developed by Asher Biotherapeutics. OPDIVO is a registered trademark of Bristol-Myers Squibb Company. KEYTRUDA is a registered trademark of Merck & Co., Inc. OCREVUS is a registered trademark of Genentech, Inc. Non-GAAP Financial Measures In this news release, management has presented its operating results for the fourth quarters and full years of 2025 and 2024, in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on a non-GAAP basis. In addition, management has presented its full year 2026 EPS and tax guidance in accordance with GAAP and on a non-GAAP basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, divestitures, restructuring and certain other items from the related GAAP financial measures. Management has presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the fourth quarters and full years of 2025 and 2024. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP. Management has also presented Earnings Before Interest, Taxes, Depreciation and Amortization (EBITDA) and debt leverage ratio for 2025, both of which are non-GAAP financial measures. EBITDA is computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income. Debt leverage ratio is calculated as the ratio of GAAP total debt to EBITDA. The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor's overall understanding of the financial performance and prospects for the future of the Company's normal and recurring business activities by facilitating comparisons of results of normal and recurring business operations among current, past and future periods. The Company believes that FCF provides a further measure of the Company's liquidity. The Company believes its debt leverage ratio provides a supplemental operating metric for the full year period as it compares the amount of cash generated by our operations for the year. The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning internally to evaluate the performance of the business, including to allocate resources and to evaluate results relative to incentive compensation targets. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. About Amgen Amgen discovers, develops, manufactures and delivers innovative medicines to fight some of the world's toughest diseases. Harnessing the best of biology and technology, Amgen reaches millions of patients with its medicines. More than 45 years ago, Amgen helped establish the biotechnology industry at its U.S. headquarters in Thousand Oaks, California, and it remains at the cutting edge of innovation, using technology and human genetic data to push beyond what is known today. Amgen is advancing a broad and deep pipeline and portfolio of medicines to treat cancer, heart disease, inflammatory conditions, rare diseases and obesity and obesity-related conditions. Amgen has been consistently recognized for innovation and workplace culture, including honors from Fast Company and Forbes. Amgen is one of the 30 companies that comprise the Dow Jones Industrial Average®, and it is also part of the Nasdaq-100 Index®, which includes the largest and most innovative non-financial companies listed on the Nasdaq Stock Market based on market capitalization. For more information, visit Amgen.com and follow Amgen on X, LinkedIn, Instagram, YouTube, Facebook, TikTok and Threads. Forward-Looking Statements This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. 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下面内容由ReviewMaker生成，想使用的可以私聊： 414391587@qq.com 科研人的“外挂”来了！ReviewMaker 3.0：从文献调研到万字综述，我们的AI工具帮您搞定一个基因的全面总结（以铁死亡核心分子GPX4为例）Abstract KRAS是人类癌症中最常见的突变癌基因之一，尤其在胰腺癌、肺癌和结直肠癌中高发。在过去四十年中，由于其蛋白表面光滑、与GTP亲和力高，KRAS一直被认为是“不可成药”的靶点。然而，随着对KRAS生物学功能、调控机制以及其与肿瘤微环境相互作用的深入理解，特别是近期针对KRAS G12C突变体的特异性抑制剂的成功开发，靶向KRAS治疗进入了一个新纪元。本综述旨在系统性地梳理KRAS蛋白的分子生物学特征，包括其复杂的翻译后修饰、膜定位、二聚化以及基因表达调控；深入探讨KRAS在不同肿瘤类型中的致癌作用，特别是野生型等位基因和不同突变亚型所扮演的独特角色；全面解析KRAS如何通过重塑细胞信号网络、代谢途径以及肿瘤微环境来驱动肿瘤的发生发展和免疫逃逸。此外，本综述将重点介绍当前靶向KRAS的各类前沿治疗策略，涵盖直接抑制剂、蛋白降解剂、下游通路抑制剂、合成致死策略及免疫疗法。最后，我们将剖析KRAS靶向治疗中出现的内在性和获得性耐药机制，并展望未来通过联合治疗和开发泛KRAS抑制剂来克服这些挑战的前景。1. 引言 (Introduction) RAS (Rat Sarcoma) 基因家族是首批被发现的人类癌基因，其中，Kirsten大鼠肉瘤病毒癌基因同源物 (Kirsten rat sarcoma viral oncogene homolog, KRAS) 自1982年被确认为首个在人类癌症中异常激活的癌基因以来，便一直处于癌症研究的核心地位 [1]。在过去的四十年里，对KRAS的研究极大地加深了我们对肿瘤发生和发展的理解。KRAS基因的激活突变是人类癌症中最常见的致癌驱动事件之一，在多种恶性实体瘤中广泛存在。尤其是在一些最致命的癌症中，KRAS突变频率极高，例如，接近95%的胰腺导管腺癌 (pancreatic ductal adenocarcinoma, PDAC)、约40%的结直肠癌 (colorectal cancer, CRC) 以及约33%的肺腺癌 (lung adenocarcinoma, LUAD) 均由KRAS突变驱动 [1, 2, 3]。 由于其蛋白表面光滑、缺乏明显的药物结合口袋，以及对GTP的高亲和力，KRAS在长达四十年的时间里被认为是“不可成药”(undruggable) 的靶点，这使得针对KRAS突变肿瘤的靶向治疗开发举步维艰 [4, 1]。然而，这一困境在近年被彻底打破。2013年，科学家们在KRAS G12C突变体蛋白的GDP结合状态下发现了一个可供药物结合的变构口袋（Switch-II口袋），这一里程碑式的发现为直接靶向KRAS突变体打开了大门 [5]。基于此，一系列共价抑制剂被成功开发出来，它们能够特异性地与KRAS G12C突变体中的半胱氨酸残基共价结合，将其锁定在非活性的GDP结合状态。其中，Sotorasib (AMG510) 和 Adagrasib (MRTX849) 在临床试验中取得了令人鼓舞的结果，Sotorasib更是成为首个获得美国食品药品监督管理局 (FDA) 批准上市的KRAS G12C抑制剂，标志着KRAS靶点从“不可成药”到“可成药”的历史性转变 [5, 4]。 这一突破不仅为携带KRAS G12C突变的癌症患者带来了新的希望，也极大地激发了针对其他KRAS突变亚型（如G12D、G12V等）以及泛KRAS抑制剂的研发热情。本文旨在全面综述KRAS的研究进展，将从KRAS的分子生物学特性、致癌机制、复杂的信号调控网络、多样化的治疗策略（包括直接和间接抑制剂）、药物耐药机制的探索以及未来的临床研究展望等方面进行深入探讨，以期为理解KRAS在癌症中的作用及开发更有效的治疗策略提供参考。2. KRAS蛋白的分子生物学与调控 (Molecular Biology and Regulation of the KRAS Protein) KRAS蛋白作为一种小GTP酶，在细胞信号转导中扮演着分子开关的关键角色，其功能受到从基因转录到蛋白质降解等多个层面的精密调控。对这一复杂调控网络的深入理解，为开发靶向KRAS的治疗策略提供了重要理论基础。 2.1 基因转录、剪接与翻译调控 KRAS基因表达的调控机制总结名称内容/功能引用(PMID)G-四链体 (G-quadruplex, G4)位于KRAS启动子区域，作为转录调控因子影响KRAS表达。[6, 7]小檗碱 (berberine) / 黄连素 (coptisine)结合并稳定KRAS启动子的G4结构，从而降低KRAS的mRNA水平。[7]APE1作为G4结合蛋白，促进KRAS启动子G4结构折叠，调控KRAS表达。[8]可变剪接 (Alternative splicing)产生KRAS4A和KRAS4B两种蛋白异构体，它们在致癌过程中可能发挥不同作用。[9]miR-96直接靶向并抑制KRAS的mRNA表达，在胰腺癌中发挥抑癌功能。[10]稀有密码子偏好性 (Rare codon bias)限制KRAS蛋白的翻译效率和表达水平，对肿瘤发生有复杂影响。[11, 12] KRAS蛋白的表达首先在转录水平受到调控。其启动子区域的富含GC的核酸酶超敏元件（NHPPE）能够形成G-四链体（G-quadruplex, G4）结构，这种特殊的二级结构作为转录调控因子，影响KRAS的表达 [6, 7]。研究发现，小分子配体如小檗碱（berberine）和黄连素（coptisine）能结合并稳定这种G4结构，从而显著降低癌细胞中KRAS的mRNA水平 [7]。此外，DNA修复酶APE1也被发现是一种G4结合蛋白，能够促进KRAS启动子G4结构的折叠，并通过影响转录因子MAZ的结合来调控KRAS的表达 [8]。 在转录后水平，KRAS基因通过可变剪接产生两种主要的蛋白异构体：KRAS4A和KRAS4B。这两种异构体在C末端高变区（HVR）存在差异，导致它们经历不同的翻译后修饰，并可能在致癌过程中发挥不同作用。例如，KRAS4A被证明在肺癌发生中尤为重要 [9]。此外，microRNA（miRNA）也参与KRAS的表达调控，例如miR-96可直接靶向KRAS的mRNA，抑制其表达，从而在胰腺癌中发挥抑癌基因的功能 [10]。 在翻译水平，KRAS基因的密码子偏好性也对其蛋白表达量有重要影响。KRAS基因富含稀有密码子，这天然地限制了其蛋白的翻译效率和表达水平。这种低表达特性在肿瘤发生中起着复杂的作用，一方面，过高水平的野生型KRAS蛋白反而具有肿瘤抑制活性；另一方面，肿瘤细胞在获得耐药性的过程中，可能需要克服这种密码子偏好性限制，通过增加KRAS拷贝数等方式来提高突变KRAS蛋白的表达量 [11, 12]。2.2 翻译后修饰与亚细胞定位 表1. 调控KRAS亚细胞定位的关键分子及其功能名称内容/功能引用(PMID)法尼基化修饰KRAS锚定到细胞膜的第一步。[13]PDEδ识别并捕获错误定位到内膜系统的KRAS。[14, 15]Arl2辅助PDEδ将KRAS释放到核周膜区域。[14, 15]SNARE蛋白 (SNAP23, SNAP29, VAMP3)介导囊泡运输，将KRAS重新转运并富集到质膜。[14, 16]SNORD50A/B负向调控KRAS的质膜定位，抑制其与SNARE蛋白的邻近性。[16]鞘糖脂 (Glycosphingolipids)维持KRAS在质膜上的定位和纳米级空间组织。[17] KRAS蛋白的功能高度依赖于其在细胞质膜上的正确定位，而这一过程由一系列复杂的翻译后修饰（Post-Translational Modifications, PTMs）和蛋白转运机制共同调控。新合成的KRAS蛋白首先在胞质中经历法尼基化修饰，这是其锚定到细胞膜上的第一步 [13]。然而，仅靠法尼基化不足以实现其向质膜的特异性富集。 KRAS蛋白的亚细胞定位是一个动态循环过程。错误定位到内质网等内膜系统的KRAS可被胞质中的可溶性蛋白PDEδ识别并“捕获”，随后在Arl2蛋白的辅助下被释放到核周膜区域 [14, 15]。之后，KRAS通过静电相互作用被捕获在再循环内体（recycling endosome），最终通过SNARE蛋白（如SNAP23, SNAP29, VAMP3）介导的囊泡运输途径被重新转运并富集到质膜上 [14, 16]。这一过程受到小GTP酶超家族成员SNORD50A/B的负向调控，它们通过抑制KRAS与SNARE蛋白的邻近性来拮抗其质膜定位 [16]。此外，细胞代谢状态也深刻影响KRAS的定位，例如糖酵解通路衍生的特定鞘糖脂（glycosphingolipids）对于维持KRAS在质膜上的定位和纳米级空间组织至关重要 [17]。2.3 蛋白稳定性与降解 调控KRAS蛋白稳定性的关键分子及其功能名称内容/功能引用(PMID)JOSD2去泛素化酶，直接与KRAS突变体作用并使其稳定，形成正反馈回路加速肿瘤生长。[18]NDRG3 / USP9X支架蛋白NDRG3促进去泛素化酶USP9X与KRAS的相互作用，从而上调KRAS蛋白表达。[19]AIMP2-DX2通过阻断E3连接酶Smurf2与KRAS的接触，阻止其被泛素化降解，从而稳定KRAS。[13]LZTR1介导经典的泛素依赖性降解通路。其功能受损会导致野生型KRAS水平升高。[20]REGγ (NRF2/REGγ通路)KRAS突变通过NRF2上调REGγ，增强ATP和泛素非依赖性的蛋白酶体降解通路。[21] KRAS蛋白的丰度受到泛素-蛋白酶体系统的严密调控，其稳定性是决定其致癌活性的关键因素。多种去泛素化酶（DUBs）被发现能够移除KRAS上的泛素链，从而保护其免于降解，延长其半衰期。例如，在结直肠癌中，去泛素化酶JOSD2可以直接与多种KRAS突变体相互作用并使其稳定。有趣的是，KRAS突变体又能反过来抑制JOSD2的E3泛素连接酶CHIP的活性，形成一个JOSD2/KRAS正反馈回路，从而显著加速肿瘤生长 [18]。另一项研究发现，支架蛋白NDRG3能够促进去泛素化酶USP9X与KRAS的特异性相互作用，从而上调KRAS蛋白的表达 [19]。 相反，一些蛋白则通过促进KRAS的泛素化降解来发挥肿瘤抑制作用。例如，肿瘤抑制因子AIMP2的剪接变体AIMP2-DX2，在KRAS法尼基化之前与其结合，通过竞争性阻断E3泛素连接酶Smurf2与KRAS的接触，阻止其被泛素化介导的降解，从而增强KRAS驱动的肿瘤发生 [13]。此外，LZTR1介导的降解通路也至关重要，该通路的受损会导致野生型KRAS蛋白水平升高，从而驱动对RAS抑制剂的内源性耐药 [20]。除了经典的泛素依赖性降解，研究还发现KRAS突变可通过NRF2上调REGγ，增强ATP和泛素非依赖性的蛋白酶体降解通路，这为泛KRAS抑制剂的开发提供了新思路 [21]。2.4 磷酸化、二聚化与其他相互作用调控 调控KRAS活性的关键分子与机制总结名称内容/功能引用(PMID)PKC / Ser-181磷酸化蛋白激酶C（PKC）磷酸化KRAS的Ser-181位点，此修饰对突变KRAS的致癌功能至关重要。[22]HNRNPA2B1与KRAS G12V相互作用，调节其磷酸化水平，影响胰腺癌细胞的KRAS依赖性。[23]Src激酶磷酸化KRAS的Tyr32和Tyr64位点，导致GTPase循环停滞并削弱与下游效应子的结合。[24]SHP2对KRAS进行去磷酸化，恢复其正常的GTPase循环动态。[24]野生型KRAS等位基因通过形成异源二聚体抑制突变KRAS的致癌活性；其存在是MEK抑制剂耐药性的原因之一。[25, 26, 27]野生型KRAS杂合性丢失(LOH)增强突变KRAS信号（尤其是MAPK通路），促进肿瘤起始，并使肿瘤对MEK抑制剂敏感。[26, 27, 25]SHANK3支架蛋白，与激活的KRAS结合，通过与RAF竞争来限制MAPK/ERK信号，抑制它可诱导“信号超载”凋亡。[28] KRAS蛋白的活性还受到磷酸化、二聚化以及与其他蛋白相互作用的精细调控。 磷酸化修饰：磷酸化是调节KRAS活性的重要机制。位于其C末端高变区的丝氨酸181（Ser-181）位点的磷酸化被证明对突变KRAS的致癌功能至关重要。蛋白激酶C（PKC）可催化该位点的磷酸化，磷酸化模拟突变体S181D展现出更强的成瘤能力，而不可磷酸化突变体S181A则无法诱导肿瘤形成 [22]。此外，异质性核糖核蛋白HNRNPA2B1能与KRAS G12V相互作用，并调节其磷酸化水平，进而影响胰腺癌细胞的KRAS依赖性 [23]。酪氨酸磷酸化也扮演着重要角色，Src激酶可磷酸化KRAS的Tyr32和Tyr64位点，导致其构象改变，GTPase循环停滞并削弱与下游效应子的结合；而蛋白酪氨酸磷酸酶SHP2则能对KRAS进行去磷酸化，恢复其正常的GTPase循环动态 [24]。 二聚化与等位基因相互作用：KRAS蛋白可以在质膜上形成同源或异源二聚体，这一过程深刻影响其信号输出。野生型（WT）KRAS等位基因通常对突变KRAS的致癌活性具有抑制作用，这种抑制效应部分是通过形成突变型-野生型异源二聚体来实现的 [25]。当肿瘤细胞发生杂合性丢失（LOH），即野生型KRAS等位基因缺失时，突变KRAS的致癌信号（尤其是MAPK通路）会显著增强，从而促进肿瘤的起始 [26, 27]。有趣的是，野生型KRAS的缺失虽然加速了肿瘤起始，但在某些模型中却可能抑制肿瘤的进展和转移 [27, 26]。这种复杂的双重作用凸显了KRAS等位基因剂量在肿瘤不同阶段扮演的不同角色。同时，野生型KRAS的存在是导致MEK抑制剂耐药性的原因之一，而野生型等位基因的缺失则会使肿瘤细胞对MEK抑制剂变得敏感 [25, 26, 27]。 其他相互作用蛋白：除了经典的上下游分子，许多新发现的相互作用蛋白也参与调控KRAS的功能。例如，支架蛋白SHANK3能与激活状态的KRAS（包括突变体）结合，通过与RAF竞争结合位点来限制下游MAPK/ERK信号的过度激活，将信号维持在一个最佳水平。因此，抑制SHANK3会导致ERK信号“过载”，从而诱导KRAS突变癌细胞的凋亡，这为治疗KRAS突变癌症提供了一种全新的“信号超载”策略 [28]。 综上所述，KRAS蛋白的生命周期受到一个多层次、动态且高度整合的调控网络所控制。从基因表达的源头，到翻译后修饰、蛋白稳定性、亚细胞穿梭，再到与其他分子的复杂相互作用，每一个环节都为KRAS的功能提供了精细的调校机制。这些复杂的调控节点不仅揭示了KRAS致癌活性的分子基础，也为开发新型、多角度的抗癌疗法开辟了广阔的前景。3. KRAS在肿瘤发生发展中的多维角色 (The Multidimensional Role of KRAS in Tumorigenesis and Progression) KRAS在肿瘤发生发展中的多维角色及相关分子机制总结名称/因素内容/功能引用(PMID)Kras G12D (内源性水平)引起细胞增殖和运动能力增强，但不足以完成恶性转化。[29]KrasG12D (结肠上皮)导致增生性息肉样结构，但不扩增干细胞池，恶性潜能较低。[30]PIK3CA 突变与 KRAS(G12D) 协同作用，显著加速肺肿瘤的发生。[31]AP-1/IL-1α/p62/NF-κB 信号轴在胰腺癌中，KrasG12D通过此信号轴持续激活NF-κB通路。[32]KRAS 抑制/敲除在胶质母细胞瘤和胰腺癌模型中导致肿瘤消退，体现“癌基因成瘾”。[33, 34]PI3K 依赖的 MAPK 信号通路作为KRAS抑制的耐药机制，维持胰腺癌细胞存活。[35]YAP1 信号通路激活后可绕过对KRAS的依赖，恢复肿瘤细胞的生存和增殖。[36, 37]FOSL1 (转录因子)连接KRAS致癌信号与有丝分裂机器（如AURKA），是KRAS驱动癌症的关键脆弱性。[38]KRAS 突变亚型 (G12C, G12V, G12D)在蛋白质行为、信号转导和临床预后方面表现出显著差异。[39]KRAS 拷贝数增加增强糖酵解转换和代谢重编程。[40]野生型 KRAS 等位基因缺失增强致癌信号，促进所有RAS亚型激活，加速白血病发生。[41]代谢重编程 (葡萄糖)KRAS刺激葡萄糖摄取，并将其导入己糖胺生物合成途径（HBP）和戊糖磷酸途径（PPP）。[34]MAPK-MYC-RPIA 信号轴KRAS通过此信号轴上调核苷酸的生物合成。[42]FASN (脂肪酸合酶)被KRAS激活，促进脂肪生成。[43]ELOVL6 (脂肪酸延长酶)调控KRAS-G12V蛋白的稳定性。[44]巨噬细胞吞饮作用 (Macropinocytosis)KRAS突变细胞通过此作用获取铜，并上调ATP7A以避免铜毒性。[45]PCSK9被KRAS上调以调控胆固醇代谢，促进GGPP积累。[46]CD47 ("别吃我"信号)KRAS通过PI3K/STAT3/miR-34a轴上调CD47，抑制巨噬细胞吞噬，促进免疫逃逸。[47]COX2/PGE2KRAS诱导COX2表达，其产物PGE2促进对免疫检查点抑制剂的抵抗。[48]KRAS C118位点氧化一种翻译后修饰，介导KRAS的氧化还原依赖性激活。[49]PIP5K1A (互作蛋白)作为KRAS特异性的互作蛋白，对其功能进行精细调控。[50]PROTAC 降解剂靶向GTP负载的KRAS(on)状态的新型治疗策略。[51]广谱 KRAS 抑制剂新一代靶向KRAS的治疗方法。[52, 53] KRAS基因的激活突变是多种人类癌症中最常见的驱动因素之一，其在肿瘤的起始、进展和维持中扮演着复杂而多维的角色。深入理解KRAS突变如何从不同层面重塑细胞生物学行为，对于开发有效的治疗策略至关重要。 在肿瘤起始阶段，KRAS突变通常被认为是关键的“第一次打击”，但其本身往往不足以完成恶性转化。例如，在小鼠体细胞中通过基因敲入方式引入内源性水平的Kras G12D突变，虽然能引起细胞增殖和运动能力增强等显著的表型变化，但并不足以使细胞完全转化 [29]。在结肠上皮中，激活KrasG12D突变可导致类似于人类增生性息肉（HPPs）的锯齿状隐窝结构和分化异常，但并不会扩增干细胞池，这解释了为何携带KRAS突变的HPPs恶性潜能较低 [30]。这些发现表明，KRAS突变需要与其他遗传或环境因素协同作用才能驱动肿瘤的全面发展。例如，PIK3CA基因的激活突变能够与KRAS(G12D)协同，显著加速和增强肺肿瘤的发生 [31]。同样，在胰腺癌的发生过程中，KrasG12D需要通过激活AP-1诱导IL-1α，进而启动IL-1α/p62前馈循环来持续激活NF-κB信号通路 [32]。 对于已形成的肿瘤，许多研究证实其生长和存活高度依赖于持续的KRAS信号，这一现象被称为“癌基因成瘾”（oncogene addiction）。在胶质母细胞瘤和晚期胰腺导管腺癌（PDAC）的小鼠模型中，抑制或敲除突变KRAS的表达能够导致肿瘤细胞凋亡、肿瘤消退，并显著延长生存期 [33, 34]。然而，KRAS的“成瘾性”并非绝对。研究发现，一部分胰腺癌细胞在KRAS功能完全丧失后仍能存活，这些细胞通过激活磷脂酰肌醇3-激酶（PI3K）依赖性的MAPK信号通路来维持其生存 [35]。更有趣的是，KRAS的缺失反而揭示了其在抑制转移相关基因表达中的作用 [35]。此外，肿瘤细胞可以通过激活YAP1信号通路来绕过对KRAS的依赖，从而在KRAS被抑制后恢复生存和增殖能力 [36, 37]。这些发现揭示了肿瘤细胞为抵抗KRAS靶向治疗而演化出的复杂适应性机制。 KRAS突变通过广泛的转录和信号重编程来发挥其致癌功能。突变KRAS能够触发一个特定的转录印记，该印记可用于对不同来源的人类癌症进行分类 [29]。例如，转录因子FOSL1被确定为KRAS驱动的肺癌和胰腺癌中的一个关键脆弱性，它将KRAS致癌信号与有丝分裂机器（如AURKA激酶）联系起来，揭示了新的治疗靶点 [38]。值得注意的是，不同的KRAS突变亚型（如G12C、G12V、G12D）在蛋白质行为、信号转导和临床预后方面表现出显著差异 [39]。此外，突变KRAS的拷贝数也至关重要，拷贝数增加的细胞表现出更强的糖酵解转换和代谢重编程 [40]。野生型KRAS等位基因的缺失也能增强致癌信号，促进所有RAS亚型的激活，从而加速白血病的发生 [41]。 在代谢层面，KRAS突变对肿瘤细胞的代谢网络进行了系统性重塑，以满足其快速增殖的能量和生物合成需求。致癌性KRAS通过刺激葡萄糖摄取，并将葡萄糖中间产物导入己糖胺生物合成途径（HBP）和戊糖磷酸途径（PPP），来维持肿瘤生长 [34]。特别是，KRAS通过MAPK-MYC-RPIA信号轴上调核苷酸的生物合成 [42]。KRAS还能激活脂肪酸合酶（FASN），促进脂肪生成 [43]，并通过调控脂肪酸延长酶ELOVL6的活性来影响自身蛋白的稳定性，抑制ELOVL6可诱导KRAS-G12V降解 [44]。更有研究发现，KRAS突变细胞通过巨噬细胞吞饮作用（macropinocytosis）获取铜，并上调铜外排蛋白ATP7A以避免铜毒性，从而对铜的生物利用度产生特殊依赖 [45]。同时，KRAS突变还通过上调PCSK9来调控胆固醇代谢，促进对KRAS激活至关重要的GGPP的积累 [46]。 KRAS的致癌作用还延伸至肿瘤细胞外部，通过重塑肿瘤微环境（TME）来促进免疫逃逸。致癌KRAS信号通过PI3K/STAT3通路抑制miR-34a的表达，从而上调其靶基因CD47的表达。CD47作为一种“别吃我”信号，能够抑制巨噬细胞对肿瘤细胞的吞噬作用，帮助肿瘤逃避先天免疫监视 [47]。此外，KRAS还能诱导COX2的表达，后者通过其产物前列腺素E2（PGE2）促进对免疫检查点抑制剂（ICB）的抵抗 [48]。这些发现表明，KRAS突变不仅驱动细胞内信号，还主动营造了一个免疫抑制的微环境。 综上所述，KRAS在肿瘤中的角色是多维度的，涉及细胞自主性的增殖、存活、代谢和转录重编程，以及与肿瘤微环境的复杂互作。KRAS蛋白的不同突变亚型、表达水平、翻译后修饰（如C118位点的氧化还原依赖性激活） [49] 乃至其特异性的互作蛋白（如PIP5K1A） [50] 都对其功能产生了精细的调控。对这些多维角色的深入理解，不仅揭示了KRAS驱动癌症的复杂性，也为开发新型治疗策略，如靶向GTP负载的KRAS(on)状态的PROTAC降解剂 [51] 或广谱KRAS抑制剂 [52, 53]，提供了新的理论基础和靶点。4. KRAS与肿瘤微环境的相互作用 (Interaction between KRAS and the Tumor Microenvironment) KRAS突变调控肿瘤微环境的关键分子与机制名称内容/功能引用(PMID)炎症与细胞因子网络NF-κB核心炎症枢纽，被致癌性KRAS激活，驱动炎性表型。[54, 55]IL-1α被KRAS G12D诱导，激活NF-κB并形成正反馈回路，持续放大炎症信号。[32]IL-1β来源于宿主髓系细胞，加剧KRAS突变肿瘤对IKKα的依赖，促进CXCL1分泌。[56]CCL5 / IL-6由KRAS信号通过TBK1/IKKε调控，形成支持肿瘤发生的自分泌细胞因子回路。[57]CXCR2配体 (KC, MIP-2)由肿瘤细胞高表达，招募中性粒细胞和内皮细胞，促进炎症和血管生成。[58]Twist被KRAS上调，抑制p16 INK4A，从而抑制炎症相关的细胞衰老，帮助肿瘤启动。[59, 60]基质与细胞外基质重塑IGF1R/AXL-AKT轴在癌相关成纤维细胞(CAFs)中被激活，向肿瘤细胞发出往复信号，调控其增殖与凋亡。[61]TFCP2 / BMP4 / WNT5BKRAS激活TFCP2，上调BMP4/WNT5B，将CAFs转化为促进血管生成的富脂CAFs。[62]KRAS-ITGA3-SRC轴介导KRAS信号与细胞外基质(ECM)的相互作用，影响早期肺癌的细胞状态。[63]免疫逃逸PD-L1 / CXCL10 / CXCL11KRAS G12D突变导致其表达/分泌减少，造成免疫抑制微环境。[64]CD47"别吃我"信号，被KRAS通过PI3K/STAT3/miR-34a轴上调，抑制巨噬细胞吞噬。[47]CSF2 / 乳酸由KRAS突变细胞分泌，将巨噬细胞重编程为促肿瘤的M2样肿瘤相关巨噬细胞(TAMs)。[65]COX2 / PGE2KRAS上调COX2，通过前列腺素E2(PGE2)介导对免疫检查点抑制剂的耐药。[48]circATXN7被KRAS激活的环状RNA，使肿瘤特异性T细胞对活化诱导的细胞死亡更敏感。[66]治疗耐药FGFR1 / AXL (RTKs)被TME中的生长因子激活，介导对KRAS G12C抑制剂的适应性耐药。[67, 68, 69]整合素 / FAK其信号通路是重要的耐药机制，抑制FAK可与KRAS抑制剂产生协同效应。[70]细胞外囊泡 (EVs)将致癌性KRAS蛋白或mRNA传递给周围细胞，增强化疗耐药性。[71] KRAS突变的致癌作用远不止于细胞自主性效应。越来越多的证据表明，KRAS突变通过重塑肿瘤微环境（Tumor Microenvironment, TME），主动建立一个有利于肿瘤生长、血管生成、侵袭和免疫逃逸的“生态位”。这种相互作用是双向的，即KRAS突变细胞改变TME，而TME反过来又影响肿瘤细胞的行为和治疗反应 [72, 73]。 4.1 KRAS驱动的炎症和细胞因子网络 KRAS突变肿瘤的一个显著特征是其炎性表型。致癌性KRAS能够通过多种机制激活NF-κB信号通路，这是调控炎症反应的核心枢纽 [54, 55]。例如，在胰腺导管腺癌（PDAC）中，KRAS G12D突变可激活AP-1，诱导IL-1α的表达，进而激活NF-κB，并形成IL-1α/p62正反馈回路，持续放大炎症信号 [32]。在恶性胸腔积液中，宿主髓系细胞来源的IL-1β能够加剧KRAS突变肿瘤细胞对IKKα的依赖，促进CXCL1的分泌，从而加剧局部炎症 [56]。此外，KRAS信号还通过TBK1/IKKε激酶调控自分泌的CCL5和IL-6，形成一个支持肿瘤发生的细胞因子回路 [57]。在KRAS诱导的肺腺癌模型中，肿瘤细胞高表达趋化因子受体CXCR2的配体（如KC和MIP-2，人CXCL8的同源物），这些配体招募中性粒细胞和内皮细胞，促进炎症和血管生成 [58]。值得注意的是，外界因素如高脂饮食可通过上调环氧合酶-2（COX2）加剧炎症反应，从而激活致癌性Kras并诱导PDAC的发生 [74]。然而，KRAS的作用也具有复杂性，在肿瘤起始阶段，它可以通过上调Twist抑制p16 INK4A的表达，从而抑制炎症相关的细胞衰老，使细胞得以逃脱生长停滞，启动肿瘤发生 [59, 60]。 4.2 KRAS对基质和细胞外基质的重塑 肿瘤基质是TME的重要组成部分，但研究表明，基质细胞本身通常不携带其上皮肿瘤细胞中的KRAS突变 [75]。然而，KRAS突变细胞能主动与基质细胞进行“异型细胞信号交流”（heterocellular signaling）。例如，PDAC中的KRAS G12D信号能够作用于癌相关成纤维细胞（Cancer-Associated Fibroblasts, CAFs），而活化的CAFs又通过IGF1R/AXL-AKT轴等通路向肿瘤细胞发出往复信号，从而调控肿瘤细胞的增殖、凋亡和线粒体功能 [61]。在结直肠癌（CRC）中，致癌性KRAS通过激活转录因子TFCP2，上调BMP4和WNT5B的表达，将CAFs转化为富含脂质的CAFs。这些富脂CAFs转而分泌VEGFA，促进肿瘤血管生成和疾病进展 [62]。此外，TGF-β信号通路也参与其中；在Kras驱动的胰腺癌前病变模型中，Tgfbr1单倍剂量不足会减少纤维化和淋巴细胞浸润，显示了其在肿瘤早期发展中的复杂作用 [76]。KRAS信号还可通过KRAS-ITGA3-SRC轴等途径与细胞外基质（ECM）相互作用，影响早期肺癌的细胞状态 [63]。 4.3 KRAS介导的免疫逃逸 KRAS突变肿瘤通常表现为免疫抑制性或“冷”肿瘤微环境，这为肿瘤逃避免疫监视提供了便利。研究表明，KRAS的致癌依赖性（oncogenic dependency）而非突变本身，在塑造肿瘤免疫应答中起主导作用；降低KRAS活性可以促进T细胞向肿瘤内浸润 [77, 78]。KRAS通过多种机制实现免疫逃逸。首先，特定KRAS突变亚型（如NSCLC中的G12D）与PD-L1的低表达以及T细胞趋化因子（如CXCL10/CXCL11）分泌减少相关，导致免疫抑制 [64]。其次，KRAS突变可通过PI3K/STAT3/miR-34a轴上调肿瘤细胞表面的“别吃我”信号CD47，从而抑制巨噬细胞的吞噬作用 [47]。第三，KRAS突变细胞通过分泌集落刺激因子2（CSF2）和乳酸，将巨噬细胞重编程为促进肿瘤生长的M2样肿瘤相关巨噬细胞（TAMs） [65]。第四，KRAS可通过上调COX2，经由前列腺素E2（PGE2）介导对免疫检查点抑制剂（ICB）的耐药 [48]。最近还发现，KRAS激活的环状RNA（circATXN7）能使肿瘤特异性T细胞对活化诱导的细胞死亡更加敏感，从而促进免疫逃逸 [66]。这些发现为联合KRAS抑制剂与免疫疗法（如PD-1/PD-L1阻断剂或Kras肽疫苗）提供了理论基础 [79, 80, 81]。 4.4 TME介导的治疗耐药 TME是KRAS突变肿瘤产生治疗耐药性的关键因素。当KRAS信号通路被抑制时，来自TME的旁路信号可以帮助肿瘤细胞存活。例如，对KRAS G12C抑制剂的适应性耐药常常涉及由TME中的生长因子（如FGF、GAS6）激活的受体酪氨酸激酶（RTK），如FGFR1和AXL，从而重新激活下游通路 [67, 68, 69]。整合素和黏着斑激酶（FAK）介导的信号也是一个重要的耐药机制，抑制FAK可与KRAS抑制剂产生协同抗癌效应 [70]。在多发性骨髓瘤中，骨髓微环境为KRAS突变细胞提供了庇护所，而靶向KRAS的寡核苷酸药物可在该微环境中发挥抗肿瘤作用 [82]。此外，肿瘤细胞还能通过细胞外囊泡（EVs）将致癌性KRAS蛋白或mRNA传递给周围细胞，从而增强化疗耐药性 [71]。这些由TME介导的耐药机制凸显了联合靶向KRAS和TME关键节点的治疗策略的重要性。5. 靶向KRAS突变癌症的治疗策略 (Therapeutic Strategies for KRAS-Mutant Cancers) KRAS基因突变是人类癌症中最常见的致癌驱动因素之一，尤其在胰腺癌、肺癌和结直肠癌中高发。然而，由于其蛋白表面光滑、缺乏深层疏水性口袋，以及与GTP的亲和力极高，KRAS在过去几十年中一直被认为是“不可成药”的靶点。近年来，随着对KRAS生物学功能和结构的深入理解，以及新药研发技术的突破，针对KRAS突变癌症的治疗策略取得了革命性进展。本节将系统梳理直接抑制KRAS、靶向其上下游通路、利用合成致死策略以及其他新兴疗法的最新研究进展。5.1 直接抑制KRAS蛋白 直接抑制KRAS蛋白的策略总结名称内容/功能引用(PMID)共价抑制剂 (Sotorasib)靶向KRAS G12C。与GDP结合状态下暴露的SII-P口袋中的C12残基共价结合，将KRAS锁定在无活性状态。[83, 84, 85]非共价抑制剂 (MRTX1133)靶向G12C以外的突变（如G12D）。非共价结合SII-P口袋，通过与H95等非保守残基相互作用实现选择性。不同突变亚型（如Q61H）在药物敏感性上存在差异。[86, 87, 88]大分子抑制剂 (DARPins)结合KRAS变构区域（α3/loop7/α4界面），抑制其与效应蛋白的相互作用及二聚化。[89]大分子抑制剂 (Monobodies)选择性结合活性状态的突变KRAS（如G12D, G12V/G12C），发挥抗肿瘤活性。[90, 91]蛋白降解剂 (PROTACs)基于PROTAC技术（如DARPin-VHL融合），选择性诱导突变KRAS蛋白的降解。[92]稳定α螺旋肽模拟SOS1螺旋，直接抑制KRAS的核苷酸交换。[93]聚集诱导肽基于KRAS的易聚集区域（APRs）设计，诱导突变KRAS错误折叠并失活。[94]基因编辑 (CRISPR)利用碱基编辑技术在基因层面直接校正KRAS致癌突变。[95] 直接靶向KRAS蛋白的策略在经历了长期瓶颈后，终于迎来了重大突破，主要集中在对特定突变亚型的抑制剂开发上。 等位基因特异性共价抑制剂：针对KRAS G12C突变的抑制剂是这一领域的里程碑。KRAS G12C突变体在GDP结合状态下，其12位突变的半胱氨酸残基附近会暴露一个“switch-II”口袋（SII-P）[83]。利用这一结构特征，科学家开发了能与该半胱氨酸共价结合的小分子抑制剂，将KRAS G12C锁定在无活性的GDP结合状态，从而阻断其下游信号传导 [84]。Sotorasib (AMG 510) 是首个获批上市的KRAS G12C抑制剂，其I期临床试验证实了在KRAS G12C突变的晚期实体瘤患者中的安全性与抗肿瘤活性，尤其在非小细胞肺癌（NSCLC）患者中，客观缓解率达到32.2%，疾病控制率高达88.1% [85]。这一成功激发了对其他KRAS突变亚型抑制剂的探索。 非共价抑制剂与泛KRAS抑制剂：由于G12C以外的突变（如G12D、G12V）不含可共价结合的半胱氨酸，开发非共价抑制剂成为新的方向。研究发现，SII-P作为KRAS蛋白上的一个优先药物结合位点，在多种突变体（包括G12、G13、Q61突变）中均可被非共价小分子配体靶向，且这种结合不完全依赖于GDP状态 [86]。MRTX1133是首个进入临床研究的强效、选择性KRAS G12D非共价抑制剂。其对KRAS的选择性主要依赖于与KRAS蛋白上非保守的第95位组氨酸（H95）的相互作用，而HRAS和NRAS在该位点为酪氨酸，从而实现了对KRAS亚型的特异性识别 [87]。此外，针对KRAS Q61H突变的研究发现，该突变使KRAS脱离上游调控，并对SHP2抑制剂产生耐药性，提示了不同突变亚型在信号调控和药物敏感性上的差异 [88]。 新型直接抑制策略：除了小分子抑制剂，其他创新的直接抑制策略也在不断涌现。 大分子抑制剂：设计的锚定蛋白重复蛋白（DARPins）能够结合到KRAS蛋白变构区域的α3/loop7/α4界面（H95残基附近），特异性地抑制KRAS与效应蛋白的相互作用及下游信号，甚至抑制KRAS在细胞膜上的二聚化 [89]。同样，针对KRAS G12D或G12V/G12C的单体蛋白（monobodies）也被开发出来，它们能选择性结合活性状态的突变KRAS，在体内外均显示出抗肿瘤活性 [90, 91]。 蛋白降解剂：基于PROTAC（蛋白水解靶向嵌合体）技术的KRAS降解剂是另一个前沿方向。例如，将KRAS特异性的DARPin与VHL E3连接酶融合构建的大分子降解剂，可以选择性地诱导突变KRAS蛋白的降解，从而在KRAS突变肿瘤中发挥抗癌作用 [92]。 其他创新方法：利用稳定α螺旋肽（如模拟SOS1螺旋的肽）直接抑制KRAS的核苷酸交换 [93]；或利用从KRAS蛋白序列中发现的易聚集区域（APRs）设计的合成肽，诱导突变KRAS蛋白错误折叠并丧失功能，从而抑制肿瘤生长 [94]。此外，CRISPR碱基编辑技术也被用于直接校正肿瘤细胞中的KRAS致癌突变，为基因治疗提供了新思路 [95]。5.2 靶向KRAS上下游通路和合成致死策略 靶向KRAS的间接治疗策略总结名称内容/功能引用(PMID)上游靶点：ERBB抑制剂在KRAS驱动的肺腺癌中，抑制对肿瘤发生和发展至关重要的ERBB家族RTK网络。[96]上游靶点：FGFR2 + EGFR 双重阻断在KRAS突变的胰腺癌模型中，协同作用，显著减少癌前病变形成。[97]下游靶点：MEK抑制剂 + BCL-XL抑制剂在多种KRAS突变癌细胞中诱导强烈的细胞凋亡，在动物模型中实现肿瘤消退。[98]下游靶点：G12C抑制剂 + (mTOR/IGF1R/MEK)抑制剂在KRAS G12C突变肺癌中，联合用药比单一用药显示出更强的疗效和特异性。[99]下游靶点：PI3K + MAPK通路联合抑制针对PIK3CA共突变导致的MEK抑制剂耐药性，凸显联合靶向的必要性。[100]合成致死：PLK1 + ROCK 联合抑制通过上调p21诱导KRAS突变细胞特异性的G2/M期阻滞和凋亡。[101]合成致死：CHK1 + MK2 联合抑制在KRAS突变细胞中引发有丝分裂灾难，显示强大的协同抗癌效应。[102]合成致死：TAK1 抑制在KRAS依赖的结直肠癌中，通过抑制Wnt信号通路促进细胞凋亡。[103]合成致死：GSK3 抑制在KRAS依赖性肿瘤中，通过上调c-Myc和β-catenin发挥抗肿瘤作用。[104]合成致死：BCL6 抑制在KRAS突变肺癌中，抑制其维持DNA复制的功能，导致DNA损伤和生长停滞。[105]合成致死：Ubc9 抑制/敲低抑制对KRAS驱动的肿瘤转化至关重要的SUMO化E2连接酶，从而抑制结直肠癌生长。[106]合成致死：UHRF1 敲除在KRAS突变肺癌中，导致全局DNA去甲基化，重新激活抑癌基因，抑制肿瘤生长。[107]验证失败的靶点：STK33 抑制(警示案例) 后续研究表明抑制其激酶活性对KRAS依赖性癌细胞的存活没有影响。[108, 109] 由于直接抑制KRAS蛋白（尤其是非G12C突变）仍面临挑战，且耐药性问题突出，靶向其信号通路的上下游组分或寻找其特异性的脆弱性（即合成致死）是重要的补充和联合治疗策略。 靶向上游信号：传统观念认为，KRAS突变会使其摆脱上游信号的调控。然而，越来越多的证据表明这种独立性并非绝对。例如，在KRAS驱动的肺腺癌中，ERBB家族受体酪氨酸激酶（RTKs）网络对于肿瘤的发生和发展至关重要，使用多靶点ERBB抑制剂可以有效抑制肿瘤形成 [96]。同样，在KRAS突变的胰腺癌模型中，FGFR2与EGFR协同作用，双重阻断这两个受体可显著减少癌前病变的形成 [97]。这些发现提示，抑制上游RTK信号输入是削弱KRAS致癌活性的有效途径。 靶向下游信号通路：KRAS主要通过RAF-MEK-ERK和PI3K-AKT-mTOR两条下游通路发挥作用。单独抑制MEK或PI3K通路往往效果有限，因为通路之间存在复杂的反馈激活机制。因此，联合用药成为主流策略。例如，MEK抑制剂与抗凋亡蛋白BCL-XL的抑制剂（如Navitoclax）联用，可在多种KRAS突变癌细胞中诱导强烈的细胞凋亡，并在动物模型中实现显著的肿瘤消退 [98]。对于KRAS G12C突变肺癌，将G12C抑制剂与mTOR、IGF1R和MEK抑制剂联合使用，比单一用药显示出更强的疗效和特异性 [99]。此外，PIK3CA的共突变是导致KRAS突变肿瘤对MEK抑制剂耐药的重要原因，这也凸显了联合靶向PI3K和MAPK通路的必要性 [100]。 合成致死策略：合成致死是指两个非致死性基因突变/抑制的组合导致细胞死亡的现象。针对KRAS突变背景，通过高通量筛选（如RNAi或CRISPR筛选）已发现多个合成致死靶点 [110]。 细胞周期与DNA损伤修复激酶：KRAS突变细胞常表现出内在的基因毒性压力，使其对细胞周期检查点激酶抑制剂敏感。研究发现，联合抑制PLK1和ROCK可通过上调p21诱导KRAS突变细胞特异性的G2/M期阻滞和凋亡 [101]。类似地，联合抑制CHK1和MK2可在KRAS突变细胞中引发有丝分裂灾难，显示出强大的协同抗癌效应 [102]。 信号通路节点：转化生长因子β活化激酶1（TAK1）在KRAS依赖的结直肠癌中是关键的生存激酶，抑制TAK1可通过抑制Wnt信号通路促进细胞凋亡 [103]。糖原合成酶激酶3（GSK3）也被证明是KRAS依赖性肿瘤生长所必需的，抑制GSK3可上调c-Myc和β-catenin，从而发挥抗肿瘤作用 [104]。 转录与表观遗传调控因子：B细胞淋巴瘤因子6（BCL6）作为KRAS-MAPK通路的下游靶点，在维持KRAS突变肺癌细胞的DNA复制中起关键作用，抑制BCL6可导致DNA损伤和生长停滞 [105]。SUMO化修饰通路中的E2连接酶Ubc9对于KRAS驱动的肿瘤转化至关重要，敲低Ubc9可有效抑制结直肠癌的生长 [106]。表观遗传调控因子UHRF1在KRAS突变肺癌中也是一个特异性脆弱性靶点，敲除UHRF1导致全局DNA去甲基化，重新激活抑癌基因，从而抑制肿瘤生长 [107]。 失败的靶点：值得注意的是，并非所有最初发现的潜在靶点都经得起验证。丝氨酸/苏氨酸激酶STK33曾被认为是KRAS的合成致死伴侣，但后续多项研究，包括使用RNAi和特异性小分子抑制剂（如BRD-8899），均表明抑制STK33的激酶活性对KRAS依赖性癌细胞的存活没有影响 [108, 109]。这为合成致死策略的靶点验证提供了重要警示。5.3 靶向KRAS依赖的其他脆弱性 靶向KRAS依赖的其他脆弱性的策略总结名称内容/功能引用(PMID)SLC7A5氨基酸转运蛋白，KRAS突变结直肠癌细胞依赖其满足蛋白质合成需求。[111]SLC7A11 / GSH合成胱氨酸/谷氨酸反向转运蛋白及谷胱甘肽合成途径，与KRAS突变肺腺癌细胞存在合成致死关系。[112]ATF4 / 天冬酰胺合成KRAS通过ATF4通路调控天冬酰胺合成，使肿瘤细胞对天冬酰胺酶敏感。[113]GLUT1 / 高剂量维生素C转运氧化型维生素C（DHA），导致ROS积累并抑制糖酵解，选择性杀死KRAS突变细胞。[114]多胺代谢 / 铁死亡逃逸KRAS突变肿瘤的依赖机制，联合靶向可增强KRAS抑制剂疗效。[115, 116]PDEδ / ORP5/ORP8负责将KRAS转运至质膜的蛋白，抑制其功能可阻断KRAS信号。[117]USP5 / Ubc9 (去泛素化/SUMO化)调控KRAS稳定性和活性的翻译后修饰相关酶，具有治疗潜力。[118, 106]KLF5转录因子，KRAS在肠道肿瘤发生中的重要下游介质。[119]RASH3D19介导正反馈环路以再激活RAS通路，靶向其可克服KRAS抑制剂的适应性耐药。[120] 除了经典的信号通路，KRAS突变还导致肿瘤细胞在代谢、蛋白稳态和生存环境等方面产生新的依赖性，这些依赖性也构成了潜在的治疗靶点。 靶向代谢重编程：KRAS突变肿瘤细胞表现出独特的代谢重编程特征。 氨基酸代谢：KRAS突变结直肠癌细胞对氨基酸转运蛋白SLC7A5高度依赖，以满足其旺盛的蛋白质合成需求 [111]。在肺腺癌中，KRAS突变细胞对胱氨酸/谷氨酸反向转运蛋白SLC7A11和谷胱甘肽（GSH）合成途径也表现出合成致死依赖性 [112]。此外，KRAS通过ATF4通路调控天冬酰胺的生物合成，使肿瘤细胞对天冬酰胺酶敏感 [113]。 糖酵解与氧化应激：KRAS突变细胞表现出增强的糖酵解。利用这一特性，高剂量的维生素C可通过其氧化形式（DHA）被GLUT1转运蛋白大量摄入，耗尽细胞内GSH，导致活性氧（ROS）积累并抑制糖酵解关键酶GAPDH，从而选择性地杀死KRAS突变细胞 [114]。 其他代谢通路：KRAS突变肿瘤还可能依赖于多胺代谢和铁死亡逃逸等机制，联合靶向这些通路与KRAS抑制剂可增强疗效 [115, 116]。 靶向KRAS蛋白定位与翻译后修饰：KRAS蛋白必须正确定位到细胞膜上才能发挥功能。抑制其膜定位过程是另一条思路。例如，抑制负责将KRAS从内膜系统转运至质膜的蛋白（如PDEδ、ORP5/ORP8）可以有效阻断KRAS信号 [117]。此外，一些翻译后修饰，如泛素化和SUMO化，也参与调控KRAS的稳定性和活性，靶向相关的酶（如去泛素化酶USP5或SUMO化连接酶Ubc9）已显示出治疗潜力 [118, 106]。 靶向协同通路与反馈机制：KRAS突变肿瘤的生长不仅依赖于其自身，还依赖于其他协同通路。例如，转录因子KLF5是KRAS在肠道肿瘤发生中的重要下游介质 [119]。同时，KRAS抑制剂的使用会激活多种反馈通路，导致耐药。例如，RASH3D19介导了一个正反馈环路，促进RAS通路的再激活，靶向RASH3D19有望克服对KRAS抑制剂的适应性耐药 [120]。 综上所述，针对KRAS突变癌症的治疗策略已经从“不可成药”的困境中走出，进入了以直接抑制剂为核心，结合靶向合成致死、代谢重编程和免疫微环境等多维度联合治疗的新时代。尽管耐药性仍然是巨大挑战，但对KRAS信号网络和肿瘤脆弱性的深入理解，正不断为开发更有效、更持久的治疗方案提供新的机遇。6. KRAS靶向治疗的耐药机制 (Mechanisms of Resistance to KRAS-Targeted Therapy) 表1. KRAS靶向治疗的耐药机制总结名称内容/功能引用(PMID)基因组/转录组层面KRAS等位基因扩增突变型Kras等位基因拷贝数增加，导致靶蛋白水平升高，使抑制剂浓度不足。[121, 122]KRAS二次获得性突变改变药物结合口袋的构象或激活KRAS，使其不依赖GTP/GDP循环，从而阻止抑制剂结合。[123]旁路激活：上游RTKEGFR、FGFR、IGF-IR等受体酪氨酸激酶被激活，绕过KRAS直接激活下游MAPK通路。[124, 125, 126]旁路激活：PI3K/AKT/mTORPIK3CA等基因的共存突变或反馈性激活，使肿瘤生长不依赖于MEK/ERK信号。[127, 128, 129, 130]旁路激活：YAP1转录共激活因子YAP1扩增和激活，通过SDC1增强营养获取和多条RTK通路激活。[37, 131]旁路激活：LCK/PAK1/β-Catenin在KRAS依赖的非小细胞肺癌中，形成信号网络作为潜在的旁路通路。[132]转录/转录后调控：eIF5A-PEAK1eIF5A-PEAK1正反馈环路异常上调，导致KRAS癌蛋白积累。[133]转录/转录后调控：lncRNA ST8SIA6-AS1通过调控PLK1/c-Myc轴赋予肿瘤原发性和获得性耐药。[134]转录/转录后调控：NRF2KRAS上调转录因子NRF2，可能赋予细胞对靶向治疗的抗性。[135]非基因组层面表型转换：上皮-间质转化(EMT)发生EMT的细胞通过IGFR-IRS1通路维持PI3K信号的持续激活，导致耐药。[136]表型转换：细胞谱系分化肿瘤细胞分化为对药物不敏感的静息状态（如AT1样细胞）或耐药的“经典”上皮状态。[137, 138]代谢重编程：向氧化磷酸化(OXPHOS)转变细胞从依赖糖酵解转向依赖线粒体OXPHOS的药物抵抗状态，与ZBTB11上调有关。[139]代谢重编程：保护性自噬抑制KRAS/ERK通路会增强细胞的自噬通量，作为一种适应性生存机制。[140, 141]代谢重编程：铁死亡逃逸肿瘤细胞通过上调ALDH1A1或FSP1来拮抗药物诱导的铁死亡过程，从而产生耐药。[142, 143] 近年来，针对KRAS G12C突变体的共价抑制剂（如Sotorasib和Adagrasib）的问世，标志着KRAS靶向治疗取得了历史性突破，打破了KRAS“不可成药”的魔咒 [123, 144]。然而，临床实践表明，与许多靶向药物一样，患者不可避免地会产生原发性或获得性耐药，导致肿瘤复发和疾病进展，这极大地限制了这些药物的长期疗效 [145, 125]。深入理解KRAS靶向治疗的耐药机制，对于开发克服耐药的联合治疗策略至关重要。这些机制复杂多样，涉及从基因组改变到细胞表型可塑性、代谢重编程以及肿瘤微环境的动态互作等多个层面。6.1 基因组和转录组层面的耐药机制 6.1.1 KRAS基因自身的改变最直接的耐药机制源于KRAS基因本身的改变。其中，KRAS等位基因扩增是一个关键的获得性耐药机制。在小鼠模型中，对Sotorasib产生耐药的肿瘤表现出突变型Kras等位基因的扩增，导致靶蛋白水平升高，从而使抑制剂浓度不足以完全抑制其活性 [121]。临床数据也表明，KRAS突变等位基因的剂量增加与晚期疾病和不良预后相关 [122]。此外，虽然罕见，但在治疗压力下，KRAS可能出现二次获得性突变，这些突变可能改变药物结合口袋的构象，阻止抑制剂结合，或激活KRAS使其不依赖于GTP/GDP循环 [123]。 6.1.2 旁路信号通路的激活当KRAS本身被有效抑制时，肿瘤细胞可通过激活平行的“旁路”信号通路来维持其增殖和生存。 MAPK通路的再激活：这是最常见的耐药机制之一。即使KRAS被抑制，下游的MAPK通路（RAF-MEK-ERK）也可能通过多种方式被重新激活。上游受体酪氨酸激酶（RTK）的激活，如EGFR、FGFR或IGF-IR，能够绕过KRAS直接激活RAF-MEK-ERK信号 [124]。例如，在KRAS突变的结直肠癌中，PI3K信号通路主要受IGF-IR等RTK调控，而非KRAS本身，这为旁路激活提供了基础 [124]。一项对KRAS G12C抑制剂产生临床耐药的快速尸检研究发现，耐药肿瘤中MAPK通路被再激活，但并未在KRAS或其下游中介物中发现新的突变，这表明非基因突变机制（如RTK的配体依赖性激活）也参与其中 [125, 126]。 PI3K/AKT/mTOR通路的激活：PI3K/AKT/mTOR是另一条关键的生存通路。在KRAS突变肿瘤中，常常伴随PIK3CA等该通路相关基因的突变。这些共存突变可以使肿瘤生长不依赖于MEK/ERK信号，从而导致对MEK抑制剂的原发性耐药 [127, 128]。即使在没有PIK3CA突变的情况下，对KRAS的抑制也可能通过反馈机制激活PI3K/AKT通路 [129]。例如，在KRAS诱导的胰腺肿瘤中，sst2的缺失可通过激活PI3K信号促进肿瘤生长 [130]。 其他信号通路的激活：研究发现，转录共激活因子YAP1的扩增和激活是KRAS抑制后肿瘤复发的重要机制 [37]。在获得性耐药模型中，YAP1激活驱动了Syndecan-1 (SDC1)的表面定位恢复，增强了巨噬胞饮介导的营养获取和多条RTK通路的激活，从而维持肿瘤生存 [131]。此外，在KRAS依赖的非小细胞肺癌中，以LCK、PAK1和β-Catenin为中心的信号网络也被证明是潜在的旁路通路 [132]。 6.1.3 转录和转录后调控耐药性也可能源于转录和翻译水平的适应性变化。例如，一个由翻译延伸因子eIF5A和激酶PEAK1组成的正反馈调节环路可以控制KRAS癌蛋白的积累，该环路的异常上调可能导致耐药 [133]。此外，长链非编码RNA（lncRNA）如ST8SIA6-AS1可通过调控PLK1/c-Myc轴赋予肿瘤对KRAS抑制剂的原发性和获得性耐药 [134]。癌基因KRAS本身也能通过上调NRF2等转录因子赋予细胞对化疗的抗性，这一机制也可能参与靶向治疗的耐药过程 [135]。6.2 非基因组层面的耐药机制 6.2.1 细胞状态可塑性与表型转换肿瘤内部的异质性和细胞状态的可塑性是耐药的主要来源。 上皮-间质转化（EMT）：EMT已被证实是KRAS G12C抑制剂在非小细胞肺癌中产生原发性和获得性耐药的原因之一。发生EMT的细胞即使在KRAS G12C被抑制的情况下，仍能通过IGFR-IRS1通路维持PI3K信号的持续激活 [136]。 细胞谱系分化和状态转换：在KRAS驱动的肺腺癌中，KRAS抑制剂可诱导肿瘤细胞向一种静息的、类似肺泡I型（AT1）细胞的状态分化，这些细胞对药物不敏感，并在停药后迅速增殖，导致肿瘤复发 [137]。类似地，在胰腺癌中，对KRAS的抑制会富集处于“经典”上皮状态的癌细胞，这些细胞是耐药并导致疾病复发的“储备库”，而“基底样”状态的细胞则对抑制剂敏感 [138]。 6.2.2 代谢重编程代谢重编程是肿瘤细胞应对治疗压力的重要适应性策略。 向氧化磷酸化（OXPHOS）的转变：研究表明，胰腺导管腺癌（PDAC）细胞在接受KRAS抑制剂治疗后，会迅速发生代谢重编程，从依赖糖酵解转向依赖线粒体氧化磷酸化（OXPHOS）的药物抵抗状态。这一过程与转录因子ZBTB11的上调有关，通过降解ZBTB11可以逆转该代谢状态并恢复对KRAS抑制剂的敏感性 [139]。 自噬的保护性作用：抑制KRAS或其下游的ERK信号通路会意外地增强细胞的自噬通量，这是一种细胞在代谢压力下的生存机制。因此，自噬成为一种适应性耐药机制。联合使用ERK抑制剂和自噬抑制剂（如氯喹）在KRAS驱动的胰腺癌模型中显示出显著的协同抗肿瘤效果 [140, 141]。 铁死亡的逃逸：KRAS抑制剂可诱导铁死亡，但肿瘤细胞可通过上调醛脱氢酶1家族成员A1（ALDH1A1）或铁死亡抑制蛋白1（FSP1）来拮抗这一过程，从而产生耐药性 [142, 143]。 综上所述，KRAS靶向治疗的耐药机制是多维度、动态且相互关联的复杂网络。从KRAS基因自身的改变，到旁路信号通路的激活，再到细胞表型和代谢状态的深刻重塑，共同构成了肿瘤逃避药物抑制的屏障。这些发现不仅解释了单一靶向药物疗效有限的原因，也为未来的治疗策略指明了方向，即必须采取多靶点、多途径的联合治疗方案，例如将KRAS抑制剂与MEK抑制剂、SHP2抑制剂、自噬抑制剂或针对特定代谢脆弱性的药物联用，以期实现更持久和更深度的临床缓解 [140, 146]。7. 临床转化与未来展望 (Clinical Translation and Future Perspectives) KRAS靶向治疗及未来策略总结策略/靶点内容/功能引用(PMID)直接抑制剂KRAS G12C抑制剂 (Sotorasib, Adagrasib)共价抑制KRAS G12C突变体，在NSCLC、CRC、PDAC等癌种中显示出临床疗效。[154], [155], [156]KRAS G12D抑制剂 (临床前)通过与突变蛋白Asp12残基形成盐桥来特异性靶向KRAS G12D。[157]间接靶向与联合策略靶向合成致死伙伴 (CNK1, EZH2, WT1)抑制KRAS突变细胞所依赖的特定蛋白，如抑制CNK1的PH结构域或调控细胞衰老与增殖的WT1；基于等位基因特异性联合使用EZH2抑制剂。[158], [159], [160]靶向蛋白相互作用/复合物破坏KRAS与下游效应蛋白（如RAF）的相互作用或KRAS自身的二聚化，或稳定其“预激活”中间状态。[161], [162], [163]靶向野生型KRAS在某些KRAS野生型肿瘤（如HCC）中，上调的野生型KRAS也可驱动肿瘤进展，具有治疗价值。[164]未来展望与挑战克服耐药性揭示耐药机制（如旁路激活、次级突变），开发合理的联合用药策略以延缓或克服耐药。[165], [166]广谱/泛KRAS疗法 (PROTACs)开发能覆盖G12D、G12V等多种突变类型的抑制剂或基于蛋白质降解技术的降解剂。[167], [168], [169]联合免疫疗法 (ICB)将KRAS抑制剂与免疫检查点抑制剂（ICB）联合，重塑肿瘤免疫微环境，产生协同抗肿瘤效应。[170], [171]新型治疗模式 (疫苗, TCR-T)开发靶向KRAS突变新抗原的治疗性疫苗和过继性T细胞疗法（TCR-T）。[170], [172] KRAS作为首个被发现的人类肿瘤基因，在过去四十年中一直是癌症研究的焦点。然而，由于其蛋白表面光滑、缺乏深层疏水性口袋以及对GTP的高亲和力，KRAS曾一度被认为是“不可成药”的靶点 [123, 147]。随着对KRAS生物学功能的深入理解和药物研发技术的突破，特别是KRAS G12C共价抑制剂的成功，KRAS靶向治疗进入了一个全新的时代。本节将总结KRAS研究的临床意义，并对未来的研究方向和治疗前景进行展望。7.1 KRAS作为临床生物标志物的意义 KRAS突变在临床实践中的首要应用是作为预测性生物标志物。早在2008年，一项里程碑式的研究就证实，只有KRAS野生型（wild-type, WT）的转移性结直肠癌（mCRC）患者才能从抗EGFR单克隆抗体（如帕尼单抗）治疗中获益 [148]。类似地，在非小细胞肺癌（NSCLC）中，KRAS突变也被发现与EGFR酪氨酸激酶抑制剂（TKI，如吉非替尼和厄洛替尼）的原发性耐药相关 [149]。这些发现确立了KRAS突变检测在指导靶向治疗中的关键地位，避免了无效治疗带来的毒副作用和经济负担。然而，KRAS在NSCLC中作为预测标志物的价值曾一度存在争议，部分原因是早期研究样本量较小以及KRAS突变在NSCLC中的异质性 [150, 151]。 除了作为预测标志物，KRAS突变的预后价值也日益受到关注。不同KRAS突变亚型对患者预后的影响存在差异。例如，一项针对肝内胆管癌（ICC）的研究表明，不同的KRAS突变亚型与患者术后的总生存期和无病生存期显著相关，提示精细化的突变分型对于评估患者风险具有重要意义 [152]。此外，KRAS突变常与其他基因突变（如BRAF）同时存在，这种复杂的突变模式可能共同影响肿瘤的生物学行为和患者预后，提示在临床决策中需要考虑肿瘤基因组的全景信息 [153]。7.2 KRAS靶向治疗的临床转化 直接抑制剂的突破：KRAS G12C抑制剂（如Sotorasib和Adagrasib）的问世，彻底改变了KRAS突变肿瘤的治疗格局 [154]。这些药物在携带KRAS G12C突变的NSCLC和CRC患者中显示出显著的临床疗效 [155]。尽管KRAS G12C突变在胰腺导管腺癌（PDAC）中仅占1%-2%，但针对这一靶点的精准治疗同样展现了巨大潜力，为这部分难治性肿瘤患者带来了新的希望 [156]。然而，G12C突变仅占所有KRAS突变的一部分，开发针对G12D、G12V等更常见突变类型的抑制剂是当前亟待解决的挑战。已有研究设计出可通过与突变蛋白Asp12残基形成盐桥来特异性靶向KRAS G12D的抑制剂，并在临床前模型中验证了其潜力 [157]。 间接靶向与联合治疗策略：在直接抑制剂取得突破的同时，间接靶向KRAS信号通路的策略也在不断发展。 靶向合成致死伙伴：通过抑制KRAS突变细胞所依赖的特定蛋白来杀死肿瘤细胞是一种有效的策略。例如，抑制支架蛋白CNK1的PH结构域可选择性地阻断KRAS突变细胞的生长 [158]。另一项研究发现，EZH2的表达受到KRAS信号的调控，且调控通路因KRAS突变亚型（G12C依赖MEK-ERK，而G12D依赖PI3K-AKT）而异，这为基于等位基因特异性的联合用药（如EZH2抑制剂联合MEK或PI3K抑制剂）提供了理论依据 [159]。此外，调控KRAS驱动的细胞衰老与增殖平衡的转录因子WT1也可能成为新的治疗靶点 [160]。 靶向蛋白相互作用与复合物：KRAS功能的发挥依赖于其在细胞膜上的正确定位和与下游效应蛋白（如RAF）的相互作用。高分辨率的冷冻电镜技术揭示了KRAS与BRAF、MEK1和14-3-3形成的自抑制复合物结构，发现KRAS的结合本身不足以激活BRAF，还需要膜募集过程。这提示，稳定这种“预激活”中间状态可能成为一种新的治疗策略，而非仅仅阻断结合 [161]。对KRAS在膜上形成同源二聚体及其与RAF相互作用的深入研究，也为开发破坏这些关键蛋白复合物的小分子药物提供了结构基础 [162, 163]。 靶向非经典KRAS驱动的肿瘤：研究发现，在某些KRAS野生型的肿瘤中，如肝细胞癌（HCC），野生型KRAS蛋白的表达上调同样可以驱动肿瘤进展并导致对索拉非尼的耐药。这表明，靶向野生型KRAS在特定癌症中也具有重要的临床价值 [164]。7.3 未来展望与挑战 尽管KRAS靶向治疗取得了历史性突破，但仍面临诸多挑战，同时也为未来的研究指明了方向。 克服耐药性：与所有靶向药物一样，KRAS抑制剂的耐药性是限制其长期疗效的主要障碍。未来的研究需深入揭示耐药的分子机制，包括旁路激活、次级突变以及肿瘤微环境重塑等，并据此开发合理的联合用药策略以延缓或克服耐药 [165, 166]。 开发广谱及等位基因特异性疗法：当前临床获益主要局限于KRAS G12C突变患者。开发能够覆盖G12D、G12V等更多突变类型的“泛KRAS”抑制剂，或针对不同突变亚型的特异性药物，是扩大受益人群的关键 [167, 168]。基于蛋白质降解技术（如PROTACs）的KRAS降解剂，能够有效降解多种KRAS突变体，展现了广阔的应用前景 [169]。 与免疫疗法联合：越来越多的证据表明，KRAS突变能够塑造一个免疫抑制性的肿瘤微环境。因此，将KRAS抑制剂与免疫检查点抑制剂（ICB）等免疫疗法相结合，有望重塑肿瘤免疫微环境，产生协同抗肿瘤效应，是目前极具潜力的研究方向 [170, 171]。 探索新型治疗模式：除了小分子抑制剂和降解剂，其他创新的治疗方式也在积极探索中，例如靶向KRAS突变新抗原的治疗性疫苗和过继性T细胞疗法（TCR-T），这些策略旨在利用人体自身免疫系统精准清除携带KRAS突变的肿瘤细胞 [170, 172]。 深化对KRAS生物学的理解：KRAS突变不仅仅是一个简单的“开关”，其致癌过程复杂且具有组织和细胞谱系特异性。例如，在造血系统恶性肿瘤中，致癌性Kras突变本身不足以导致恶性转化，还需要二次打击事件的协同作用，且其起始靶细胞为造血干细胞 [173]。深入理解KRAS在不同肿瘤类型、不同突变亚型以及与肿瘤微环境相互作用中的独特生物学功能，将为开发更精准、更有效的治疗策略提供新的思路。 总之，KRAS研究已经从基础科学的探索成功迈向临床应用的转化。随着KRAS G12C抑制剂的成功，我们有理由相信，通过开发更广谱的抑制剂、设计更智能的联合治疗方案以及探索全新的治疗模式，人类终将攻克KRAS这个曾经“不可战胜”的癌症靶点，为广大癌症患者带来福音。8. 结论 (Conclusion) 作为发现最早、突变频率最高的癌基因之一，KRAS在过去几十年中一直是肿瘤研究的焦点。得益于分子生物学、基因组学和化学生物学的飞速发展，我们对KRAS突变体的分子结构、信号转导网络、代谢重编程及其在肿瘤发生发展中的核心驱动作用有了前所未有的深刻理解 [174, 175]。研究揭示了KRAS突变不仅通过经典的MAPK和PI3K通路驱动细胞增殖，还通过调控非编码RNA [176]、蛋白质泛素化修饰 [177]、表观遗传 [178] 和氧化还原稳态 [179] 等多种机制，在不同组织和细胞起源中启动并维持肿瘤的恶性表型 [180, 181, 182]。 在经历了漫长的“不可成药”时期后，针对KRAS G12C突变体的共价抑制剂（如Sotorasib和Adagrasib）的成功开发和临床应用，无疑是KRAS靶向治疗乃至整个精准医疗领域的里程碑式突破 [85, 183, 184]。这些药物的出现首次证明了直接靶向KRAS突变体是可行的，为攻克这一顽固靶点带来了希望。 然而，临床实践和基础研究迅速揭示了严峻的耐药性问题。无论是内源性耐药还是获得性耐药，都极大地限制了直接KRAS抑制剂的长期疗效 [185, 186]。耐药机制极为复杂，包括KRAS基因本身的扩增、旁路信号通路的激活（如受体酪氨酸激酶RTK）、细胞状态的可塑性（如上皮-间质转化）以及对化疗药物的交叉耐药性增强等 [187, 188]。此外，KRAS突变肿瘤细胞还能通过上调替代表错修复通路来应对DNA损伤，进一步增加了治疗难度 [189]。 为了克服耐药并开发更持久的治疗策略，未来的研究必须转向一个更宏观和系统的视角。整合基因组学、蛋白质组学、代谢组学等多组学数据，将有助于我们绘制出KRAS驱动的肿瘤全景图谱 [190, 191]。这不仅能揭示新的治疗靶点，更能让我们深入理解KRAS如何重塑整个肿瘤生态系统（Tumor Ecosystem），包括其与免疫细胞、基质细胞、代谢物乃至微生物群的复杂互作网络 [192, 193]。例如，KRAS突变能够通过重编程肿瘤代谢（如增强糖酵解和谷氨酰胺分解）来支持自身生长，同时也为靶向代谢通路提供了新的治疗契机 [194, 195]。在此基础上，开发更智能、更有效的个体化联合治疗策略是未来的核心方向，例如将直接KRAS抑制剂与靶向其下游或旁路信号通路的药物（如RAF/MEK抑制剂）相结合 [196]，或者联合靶向肿瘤生态系统中关键节点的疗法，以及靶向KRAS活性状态的组合疗法等 [197]。 综上所述，尽管挑战重重，但随着我们对KRAS生物学复杂性的认知不断深化，以及创新疗法的不断涌现，我们有理由相信，通过多学科交叉融合和个体化精准施策，人类终将攻克KRAS突变这一顽固的癌症驱动因素。Supplementary Studies / Further Reading补充研究/延伸阅读 除了本文先前章节中详细讨论的核心主题外，还有大量研究从不同角度扩展了我们对KRAS生物学及其在癌症中作用的理解。这些研究涵盖了共突变、非经典KRAS驱动机制、新的调控网络以及创新的治疗策略，为未来的研究和临床应用提供了重要线索。 一个关键的研究方向是探索KRAS突变与其他基因改变的相互作用及其临床意义。一项针对早期可切除非小细胞肺癌（NSCLC）的大型汇总分析表明，TP53与KRAS的共突变状态在接受辅助化疗或观察的患者中，并未显示出对总生存期或无病生存期的显著预后影响 [198]。然而，在局部晚期（III期）非鳞状NSCLC中，情况有所不同。一项多中心回顾性研究发现，在接受同步放化疗和度伐利尤单抗（durvalumab）巩固治疗的患者中，携带KRAS突变的患者其中位无进展生存期（PFS）显著短于KRAS野生型患者，这表明KRAS突变可能是该治疗方案下的一个不良预后因素 [199]。从机制上看，KRAS突变常与KEAP1功能丧失性突变在约20%的肺腺癌（LUAD）中同时发生。研究证明，这种共存状态是导致KRAS突变型LUAD在免疫和代谢方面表现出显著异质性的一个关键驱动因素，为理解肿瘤微环境和制定个性化治疗策略提供了新视角 [200]。 尽管KRAS突变在约90%的胰腺癌中起着核心驱动作用，但仍有部分胰腺癌为KRAS野生型。一项利用基因工程小鼠模型的研究揭示，p53和SMAD4的联合缺失可以在没有致癌性KRAS突变的情况下，诱导腺鳞癌亚型胰腺癌的自发形成，这为KRAS野生型胰腺癌的发生提供了重要的替代致病机制 [201]。此外，KRAS在血液系统恶性肿瘤中的作用也日益受到关注 [202]。例如，在多发性骨髓瘤（MM）中，泛素特异性蛋白酶2（USP2）被鉴定为一种新型的KRAS去泛素化酶。通过药物或基因手段抑制USP2可导致KRAS降解，从而抑制MM细胞的增殖，这提示靶向KRAS降解途径可能成为治疗相关血液肿瘤的新策略 [203]。 近年来，对KRAS信号通路上下游调控的精细机制研究取得了显著进展。研究发现，F-box蛋白FBXL6能够通过促进野生型和突变型KRAS的多聚泛素化来激活其功能，揭示了一个新的KRAS上游调控因子 [204]。在KRAS突变的结直肠癌（CRC）中，丙酮酸脱氢酶磷酸酶催化亚基1（PDP1）被发现是一个关键的进展调节因子，它作为支架蛋白增强BRAF和MEK1的相互作用，从而激活MAPK信号通路 [205]。另一项研究发现，在LUAD中，KRAS/PI3K轴驱动了通用转录因子III C亚基6（GTF3C6）的表达，后者通过调节FAK磷酸化促进肿瘤发生 [206]。此外，转录因子Miz1通过抑制原钙粘蛋白Pcdh10的表达来促进KRAS驱动的肺肿瘤发生 [207]。更有开创性的工作表明，通过在活细胞上进行蛋白质靶向的聚糖编辑，可以直接破坏KRAS信号传导，为靶向KRAS提供了全新的化学干预手段 [208]。 KRAS的功能状态与细胞内其他关键生物学过程紧密相连。例如，在LUAD中，致癌性KRAS的“成瘾”状态差异性地影响着MTH1（一种8-氧代鸟嘌呤核苷三磷酸酶）的表达和活性，而MTH1对于防止氧化核苷酸掺入基因组至关重要。抑制KRAS可导致MTH1表达下降，这揭示了KRAS状态与细胞氧化还原稳态之间的联系 [209]。在胰腺癌中，研究发现KRAS/ABHD17C/ALOX15B轴通过促进铁死亡逃逸来驱动肿瘤进展，为KRAS突变型胰腺癌提供了新的治疗靶点 [210]。 对KRAS结构和药物反应的深入研究也为治疗策略的开发提供了宝贵信息。一项基于核磁共振的研究揭示，效应蛋白（如RAF1的RBD-CRD结构域）的结合会依次改变KRAS在细胞膜上的二聚化模式，从而为RAS介导的RAF激活机制提供了新的结构见解 [211]。早期的研究已经显示出基于KRAS状态的差异化治疗潜力。例如，多激酶抑制剂索拉非尼（Sorafenib）在KRAS野生型NSCLC细胞中主要靶向B-RAF，而在KRAS突变细胞中则主要靶向C-RAF，尽管它在两种细胞中均能抑制生长 [212]。另一项研究表明，内源性突变KRAS(D13)的缺失会降低结直肠癌细胞对溶瘤病毒ReovirusT3D和奥沙利铂诱导的凋亡敏感性，但对TRAIL诱导的凋亡无影响，这提示特定KRAS突变亚型在决定治疗反应中的复杂作用 [213]。利用KRAS突变肿瘤增强的巨噬胞饮作用，研究人员开发了靶向该途径的肽-多西他赛偶联药物，实现了对胰腺癌细胞的旁观者杀伤效应，为泛KRAS突变癌症的治疗提供了新思路 [214]。最后，在临床诊断方面，对循环肿瘤DNA（ctDNA）中KRAS突变的检测显示出巨大的应用潜力，一项研究表明，治疗前在晚期NSCLC患者的ctDNA中检测到KRAS突变具有重要的临床价值 [215]。这些补充研究共同描绘了一幅更加完整和复杂的KRAS生物学图景，并不断为攻克KRAS驱动的癌症带来新的希望。References Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D Cox, Channing J Der KRAS: the Achilles' heel of pancreas cancer biology. 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