Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors

Article

作者: Gibbons, D L ; Sholl, L M ; Scalera, S ; Jänne, P A ; Maugeri-Saccà, M ; Cooper, A J ; Haradon, J ; Rodig, S J ; Zhang, J ; Awad, M M ; Gogia, P ; Ardizzoni, A ; Garbo, E ; Thummalapalli, R ; Gandhi, M M ; Alessi, J V ; Heist, R S ; De Giglio, A ; Haradon, D ; Marinelli, D ; Arbour, K C ; Ricciuti, B ; Luo, J ; Nishino, M ; Wang, X ; Di Federico, A ; Hong, L ; Nguyen, T ; Saini, A ; Elkrief, A ; Sperandi, F ; Voligny, E ; Pfaff, K ; Melotti, B ; Makarem, M ; Digumarthy, S ; Gelsomino, F ; Ladanyi, M ; Vaz, V ; Favorito, V ; Pecci, F ; Cipriani, L ; Schoenfeld, A J ; Lindsay, J ; Johnson, B E ; Heymach, J V ; Rekhtman, N ; Vokes, N I

BACKGROUNDApproximately 10% of lung adenocarcinomas (LUADs) have mucinous histology (LUAD^Muc), which is associated with a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUAD^Muc by comparing it with LUAD without mucinous histology (LUAD^non-muc) and determine the relative benefit of current treatments.PATIENTS AND METHODSPatients with LUAD from five institutions and The Cancer Genome Atlas Pan-Cancer Atlas classified as LUAD^Muc or LUAD^non-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUAD^Muc and LUAD^non-muc.RESULTSOf 4082 patients with LUAD, 9.9% had LUAD^Muc. Compared with LUAD^non-muc, patients with LUAD^Muc had a lighter smoking history (median 15 versus 20 pack-years; P = 0.008), lower programmed death-ligand 1 (PD-L1) tumor proportion score (median 0% versus 5%, P < 0.0001), and lower tumor mutation burden (median 6.8 versus 8.5 mutations/megabase, P < 0.0001). Mutations in KRAS, NKX2-1 [thyroid transcription factor 1 (TTF-1)], STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUAD^Muc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUAD^non-muc. At stage IV diagnosis, LUAD^Muc was more likely to have contralateral lung metastasis (55.2% versus 36.9%, P < 0.0001) and less likely to have brain metastases (23.3% versus 41.9%, P < 0.0001). Compared with LUAD^non-muc, LUAD^Muc cases showed lower intratumor CD8⁺, PD-1⁺, CD8⁺PD-1⁺, and FOXP3⁺ cells. Among metastatic cases receiving immune checkpoint inhibitors, compared with LUAD^non-muc (n = 1511), LUAD^Muc (n = 112) had a lower objective response rate (ORR 8.4% versus 25.9%, P < 0.0001), and shorter median progression-free survival (mPFS 2.6 versus 3.9 months, P < 0.0001) and overall survival (mOS 9.9 versus 17.2 months, P < 0.0001). Similarly, patients with LUAD^Muc had worse outcomes to chemoimmunotherapy. LUAD^Muc (n = 18) and LUAD^non-muc (n = 150) had similar ORR (16.7% versus 34.9%, P = 0.12) and mPFS (4.6 versus 5.6 months, P = 0.17) to treatment with KRAS^G12C inhibitors, but LUAD^Muc had shorter mOS (6.8 versus 10.8 months, P = 0.018).CONCLUSIONSLUAD^Muc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.

2025-02-27·Journal of Medicinal Chemistry

Identification of Structurally Novel KRAS^G12C Inhibitors through Covalent DNA-Encoded Library Screening

Article

作者: Saiki, Anne Y. ; Ma, Yingli ; Liu, Rongfeng ; Manoni, Francesco ; Zhang, Wenhan ; Lanman, Brian A. ; Cee, Victor J. ; Li, Yu ; Allen, Jennifer R. ; Leavitt, Monica ; Lopez, Patricia ; Dahal, Upendra P. ; Mukhina, Olga A. ; Rex, Karen ; Wang, Paul ; Pickrell, Alexander J. ; Kaller, Matthew R. ; Zhu, Kai ; Ma, Vu ; Lee, Heejun ; Sun, Zhen ; Li, Wencui ; Tamayo, Nuria A. ; Li, Xun ; Sun, Yaping ; Mohr, Christopher ; Huang, David ; Stellwagen, John ; Hu, Liaoyuan A. ; Dai, Dongcheng ; Wu, Wenting ; Banerjee, Abhisek ; Frohn, Michael J. ; Li, Cui ; Medina, Jose M. ; Eshon, Josephine

Covalent inhibition of the KRAS^G12C oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS^G12C inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRAS^G12C. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRAS^G12C with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects.

2025-02-01·Cancer Letters

WEE1 confers resistance to KRASG12C inhibitors in non-small cell lung cancer

Article

作者: Konno, Satoshi ; Tanaka, Kosuke ; Mori, Shunta ; Ohe, Yuichiro ; Yagishita, Shigehiro ; Liu, Jie ; Hamada, Akinobu ; Yamamoto, Gaku ; Saito, Hitoshi ; Ohashi, Akihiro ; Nakao, Takehiro ; Yatabe, Yasushi ; Shinno, Yuki ; Watanabe, Shun-Ichi ; Horinouchi, Hidehito ; Kobayashi, Susumu S ; Kitai, Hidenori ; Yamamori-Morita, Tomoko ; Yoshida, Tatsuya ; Kamata, Ryo

KRAS^G12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRAS^G12C-mutant non-small cell lung cancer (NSCLC). However, the efficacy of single-agent treatments is limited, presumably due to multiple resistance mechanisms. To overcome these therapeutic limitations, combination strategies that potentiate the antitumor efficacy of KRAS^G12C inhibitors must be developed. Through unbiased high-throughput screening of 1395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib. The combination of sotorasib and adavosertib exhibited synergistic antiproliferative activities both in vitro and in vivo, irrespective of TP53, STK11, and KEAP1 co-mutation profiles. WEE1 inhibition potentiated MCL-1-mediated apoptosis in sotorasib-treated cancer cells. Mechanistically, the combination downregulated MCL-1 protein levels by attenuating de novo translation and enhancing its degradation. WEE1 overexpression conferred resistance against sotorasib via MCL-1 upregulation. Moreover, cells that acquired sotorasib resistance profoundly upregulated both WEE1 and MCL-1 proteins, highlighting WEE1 as a crucial driver of sotorasib resistance. Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRAS^G12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRAS^G12C inhibitors, thus representing a novel therapeutic strategy for KRAS^G12C-mutant NSCLC.

项与 KRAS G12C inhibitors (Leidos Biomedical Research) 相关的新闻（医药）

2024-12-09

·Business Wire

BBO-8520 Preclinical Data Published in Cancer Discovery Supports the Potential for the First-in-Class Molecule to Provide Therapeutic Benefit in KRASG12C Mutant Tumors

SOUTH SAN FRANCISCO, Calif.--( BUSINESS WIRE )--TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, today announced the publication of preclinical data supporting the hypothesis that targeting both “ON” and “OFF” forms of KRAS G12C results in greater potency, deeper responses, and slowed development of resistance leading to significant benefits over “OFF” only KRAS G12C inhibitors approved in non-small cell lung cancer (NSCLC). The publication, titled “ Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRAS G12C ” was published in the peer-reviewed journal Cancer Discovery , a journal of the American Association for Cancer Research. Current KRAS G12C inhibitors work by binding to the inactive guanosine diphosphate (GDP)-bound “OFF” form of the protein, preventing its oncogenic activation. However, they do not directly target or inhibit the active guanosine triphosphate (GTP)-bound “ON” form. This limitation leaves KRAS G12C “ON” unaddressed, leading to adaptive resistance characterized by increased expression and activity of the active KRAS G12C “ON” state. The data in this manuscript demonstrate that BBO-8520, a first-in-class direct dual inhibitor, directly binds to both the “ON” and “OFF” states of KRAS G12C in the Switch-II/Helix3 pocket. There, it covalently modifies the target cysteine to disable effector binding to the “ON” state of KRAS G12C . In vivo , BBO-8520 demonstrates rapid target engagement and inhibition of downstream signaling, resulting in durable tumor regression in multiple tumor models, including those resistant to KRAS G12C “OFF” only inhibitors. “The aspiration to design a first-in-class, direct, dual inhibitor of the GTP-bound 'ON' and GDP-bound 'OFF' forms of KRAS G12C has been achieved,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “BBO-8520 is a dual inhibitor of KRAS G12C that provides optimal target coverage with exquisite potency, overcoming key deficiencies of 'OFF' only inhibitors, and represents a novel mechanism of action because it is the only direct inhibitor that actually blocks effector binding. Preclinical data shows that this novel mechanism delays the emergence of adaptive resistance seen with 'OFF' only inhibitors in the clinic. The potential of this approach holds significant promise for delivering enhanced clinical outcomes in patients with NSCLC.” “Using nuclear magnetic resonance (NMR) and X-ray crystallography, as well as biochemical and cell-based assays, we’ve been able to decipher the mechanism of action of this potent dual inhibitor,” said lead author Anna Maciag, PhD, Principal Scientist at Frederick National Laboratory for Cancer Research (FNLCR). “Our ability to apply the multitude of high throughput screens and assays available at FNLCR allowed for quick structure activity relationship (SAR) determination and progress.” Resistance to KRAS G12C “OFF” inhibitors primarily arises from increased KRAS G12C activity in its “ON” state. This can occur through mutant allele amplification or activation of receptor tyrosine kinases (RTKs) by growth factors. Newly synthesized KRAS is likely to bind GTP, as intracellular GTP concentrations are roughly ten times higher than GDP. As a result, upregulating the mutant protein’s transcription offers an efficient escape mechanism for cells to bypass the effects of “OFF” inhibitors. Similarly, receptor tyrosine kinase (RTK) activation can effectively overcome “OFF” only inhibitors by maintaining a high level of KRAS G12C in its “ON” state. This study shows that the presence of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) significantly impairs the potency of “OFF” inhibitors in vitro , while amplification of KRAS G12C is also detrimental in vivo . In contrast, BBO-8520 maintains exquisite potency in the presence of growth factors, mutant allele amplification, as well as when mutations are engineered to maintain KRAS G12C in the “ON” form. BBO-8520 is currently being evaluated in a Phase 1 study ( NCT06343402 ) of KRAS G12C NSCLC patients pre-treated with first generation KRAS G12C “OFF” inhibitors or with no prior KRAS G12C targeted therapy experience. The discovery of BBO-8520 was the result of a collaboration between the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Lawrence Livermore National Laboratory, and BBOT. About TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (BBOT) BridgeBio Oncology Therapeutics (BBOT) is a clinical-stage biopharmaceutical company advancing a next generation pipeline of novel small molecule therapeutics targeting RAS and PI3K malignancies. Initially formed as a subsidiary of BridgeBio, BBOT completed a $200M private financing with external investors in 2024 with the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information visit bridgebiooncology.com .

临床1期AACR会议

2024-05-02

·FierceBiotech

BridgeBio taps VCs for $200M, fueling oncology spinout's push to surpass KRAS class

Funding will support BridgeBio Oncology Therapeutics and "significant clinical inflection points over the next 18-24 months." BridgeBio Pharma has spun its Rolodex to fund a subset of its sprawling list of opportunities. Busy with launch and late-phase activities, BridgeBio has secured $200 million to equip a cancer-focused offshoot to push a pipeline led by a KRAS inhibitor through early-phase tests. In 2017, TheRas, which is now doing business as BridgeBio Oncology Therapeutics (BBOT), struck a deal with Leidos Biomedical Research that led to the licensing of a KRAS G12C inhibitor and two other assets. TheRas was a wholly owned subsidiary of BridgeBio for years but required limited funding, with R&D expenses related to the Leidos agreements totaling $3.6 million in 2023. Now, with one asset in the clinic and two approaching human testing, BridgeBio has decided to spin the molecules out to create BBOT and bring outside investors on board. The funding gives BBOT the “runway to achieve significant clinical inflection points over the next 18-24 months,” BridgeBio said. BBOT began a phase 1 trial of KRAS G12C inhibitor BBO-8520 in non-small cell lung cancer last month. The start date of the study, which will test the molecule as a single agent and in combination with Keytruda, puts the program years behind approved KRAS drugs sold by Amgen and Bristol Myers Squibb. But BBOT and its backers contend a feature of BBO-8520 could lead to better efficacy. KRAS cycles between an “on” and “off” state. Amgen’s Lumakras and BMS' Krazati target the off state, as does Roche’s challenger divarasib. BBOT believes molecules also need to inhibit KRAS in its on state to achieve optimal target coverage and prevent adaptive mechanisms of resistance. BBOT’s preclinical tests suggest BBO-8520 has advantages over Amgen, BMS and Roche’s molecules. And the biotech's researchers saw responses when the molecule was administered after the development of resistance to Lumakras. The spinout is working to generate human data on BBO-8520 while preparing to move two other assets into the clinic. BBO-10203 is designed to block an interaction between RAS and PI3Ka. In doing so, the molecule may inhibit a tumor signaling pathway without causing the high blood sugar that affects people on PI3Kα inhibitors. BBOT is aiming to start enrolling patients in a clinical trial this year. A pan-KRAS inhibitor, BBO-11818, is following close behind. Like Lumakras and Krazati, BBOT’s lead drug candidate only targets a subset of patients with KRAS mutations. BBO-11818 is designed to target the on and off states of multiple forms of KRAS, potentially making it effective in more patients. BBOT is aiming to file to study the molecule in humans next year. Eli Wallace, Ph.D., and Pedro Beltran, Ph.D., will oversee the programs as BBOT’s CEO and chief scientific officer, respectively. Wallace joined BridgeBio as CSO in residence for oncology in 2019. Beltran arrived the following year to work with Wallace on programs targeting RAS biology. The financing round was led by Cormorant Asset Management and co-led by Omega Funds. Affiliates of Deerfield Management, GV, EcoR1 Capital, Wellington Management, Enavate Sciences, Surveyor Capital, Aisling Capital, Casdin Capital and Longwood Fund also participated. Securing outside investment frees BridgeBio to spend its cash on launching acoramidis and enrolling patients in a clutch of phase 3 studies.

临床1期引进/卖出高管变更

2023-12-01

·SYNAPSE

Revolutionizing Cancer Treatment: The Emergence and Impact of KRAS G12C Inhibitors

KRAS G12C is a specific mutation of the KRAS gene that plays a crucial role in the development and progression of certain cancers. This mutation occurs in the KRAS protein, which is involved in regulating cell growth and division. In the human body, the KRAS G12C mutation leads to the overactivation of signaling pathways that promote uncontrolled cell proliferation and survival. This mutation is particularly prevalent in lung and colorectal cancers, making it an attractive target for therapeutic interventions. Efforts are underway to develop drugs that specifically inhibit the KRAS G12C mutation, with the aim of effectively treating these types of cancers. Currently, there are two KRAS G12C inhibitors approved for marketing, sotorasib and Adagrasib. On May 29, 2021, the U.S. FDA announced the accelerated approval of Lumakras (sotorasib, AMG510) developed by Amgen for the treatment of non-small cell lung cancer patients carrying the KRAS G12C mutation. The FDA’s approval is based on data from the AMG510 CodeBreaK 100 Phase 2 clinical trial (NCT03600883). This trial included 124 patients with advanced non-small cell lung cancer with the KRAS G12C mutation. The results showed an objective response rate (ORR) of 37.1%, including 3 complete responses and 43 partial responses, and a disease control rate of 80.6%. The median duration of response was 10 months. Notably, 81% of patients experienced tumor shrinkage (n = 101/124), and the average best tumor shrinkage among all patients responding to sotorasib treatment was 60%! Adagrasib (MRTX849) is the second marketed, orally optimized inhibitor specific for the KRAS G12C mutation. It irreversibly and selectively binds to KRAS G12C in its inactive state, preventing it from sending cell growth signals and causing cancer cell death. In April 2023, updated data from the Phase 2 study KRYSTAL-1 (NCTO3785249) was presented at the ASCO Annual Meeting, showing strong activity of this drug against various solid tumors, including pancreatic cancer, biliary system tumors, appendiceal cancer, ovarian cancer, etc. The results showed a total objective response rate (ORR) of 35.1% and a disease control rate (DCR) of up to 86.0%, meaning that nearly 90% of patients had their tumors shrink or stabilize to varying degrees. At the 2023 AACR conference, new data from the Phase Ib study GDC-6036 was released. 29 patients with advanced or metastatic KRAS G12C positive colorectal cancer were enrolled. These patients were all late-stage patients who had failed at least two treatment regimens and received divarasib and cetuximab treatment. The results showed that Divarasib has good clinical activity and controllable safety. 66% (n=19/29) of patients achieved unconfirmed overall responses, and 62% (n=18/29) of patients achieved confirmed overall responses. This means that over 60% of late-stage patients had significant tumor shrinkage of more than 30%! More notably, among the 5 patients who had previously received KRAS G12C inhibitor treatment, 3 patients responded to divarasib treatment, meaning that patients resistant to treatment now have a new “life-extending” option. Overall, the target KRAS G12C presents a competitive landscape with multiple companies, various indications, and different drug types. The future development of drugs targeting KRAS G12C holds great potential, especially in countries like China, where significant progress has been made. How do they work?KRAS G12D inhibitors are a type of medication or therapeutic agents that specifically target and inhibit the activity of the KRAS G12D mutation. KRAS is a gene that plays a crucial role in regulating cell growth and division. However, mutations in the KRAS gene, such as the G12D mutation, can lead to uncontrolled cell growth and contribute to the development and progression of certain cancers. From a biomedical perspective, KRAS G12D inhibitors are designed to specifically target the KRAS G12D mutation and block its signaling pathway. By inhibiting the activity of this mutated gene, these inhibitors aim to disrupt the abnormal cell growth and division, ultimately suppressing the growth of cancer cells. This targeted approach holds promise for the treatment of cancers that harbor the KRAS G12D mutation, such as certain types of lung, colorectal, and pancreatic cancers. It is important to note that KRAS G12D inhibitors are still under development and clinical trials. While they show potential as a targeted therapy for specific cancers, further research is needed to evaluate their safety, efficacy, and potential side effects. List of KRAS G12C InhibitorsThe currently marketed KRAS G12C inhibitors include: KRASG12D-LODERAnti-KRAS G12D mTCR PBL(NCI)MRTX-1133ASP 3082BI-1701963HRS-4642RMC-9805UA022DCTY-1102DN-022150For more information, please click on the image below. What are KRAS G12C inhibitors used for?KRAS G12C inhibitors are mainly used in a variety of solid tumors such as non-small cell lung cancer, pancreatic cancer, biliary system tumors, appendix cancer, ovarian cancer, etc. please click on the image below to log in and search. How to obtain the latest development progress of KRAS G12C inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of KRAS G12C inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与 KRAS G12C inhibitors (Leidos Biomedical Research) 相关的药物交易

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