作者: Zou, Huiru ; Yan, Yan ; Lian, Xiaoli ; Dai, Xiaohua ; Jiang, Shihui ; Li, Xingjiao ; Yang, Zhimou ; Li, Xinxin ; Yu, Zhaoxia ; Wang, Yue ; Wang, Guanhua

OBJECTIVES:

Enamel matrix derivative (EMD) is widely recognized for its ability to induce osteogenic and odontogenic differentiation. However, the complex composition of EMD frequently results to inconsistent experimental and clinical outcomes. Amelogenin, a key component of EMD, plays crucial roles in tooth germ development as well as in the repair and regeneration of dental tissue. In this study, an amelogenin peptide was investigated on the proliferation and odontogenic differentiation of human dental pulp cells (HDPCs).

METHODS:

The amelogenin peptide with the amino acid sequence KWYQNMIR was synthesized using solid-phase techniques. HDPCs were stimulated with various concentrations of the peptide. CCK-8 assays, alkaline phosphatase (ALP) activity measurements, quantitative reverse transcription-polymerase chain reaction, Western blot analysis, Alizarin red staining, and scanning electron microscopy were used to assess the effects.

RESULTS:

The amelogenin peptide concentrations of 100 nM and 1 μM significantly enhanced HDPC proliferation at 5 and 7 days (P < .01), with 1 μM exhibiting the most pronounced effect. Treatment with 1 μM amelogenin peptide enhanced ALP activity in HDPCs at 7 and 14 days (P < .01) and markedly upregulated the mRNA expression of DSPP, DMP-1, and RUNX-2. Western blot analysis revealed that 1 μM amelogenin peptide enhanced the protein expression of DSPP, DMP-1, and ALP in HDPCs at 7 and 14 days. Additionally, it promoted calcium deposition and mineralized nodule formation at 28 days. Importantly, the amelogenin peptide upregulated the phosphorylation level of ERK1/2 (p-ERK1/2), and the application of an ERK1/2 inhibitor suppressed HDPC differentiation.

CONCLUSIONS:

The amelogenin peptide stimulates both the proliferation and odontogenic differentiation of HDPCs via the ERK1/2 pathway. These findings suggest that the amelogenin peptide may have significant implications for regenerative dentistry, particularly in the context of dentine-pulp complex regeneration.

2025-10-01·CANCER CELL

RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition

作者: Daniyan, Anthony F. ; Weis, Kenyon ; Hanoun, Maher ; Terriou, Louis ; Young, Robert ; Mahajan, Sonia ; Reiner, Anne S. ; Rahman, Jahan ; Yoo, Sarah ; Zhang, Pu ; Singer, Michael ; Benbarche, Salima ; Abdel-Wahab, Omar ; Fox, Nina ; Haroche, Julien ; Emile, Jean-Francois ; Hershkovitz-Rokah, Oshrat ; De Lassus, Laure Farnault ; Rosenblum, Marc ; Chen, Luke Y.C. ; Sosa, Gabriela ; Maron, Maxim I. ; Francis, Jasmine H. ; Tittley, Steven ; Rotemberg, Veronica ; Rampal, Raajit K. ; Petrova-Drus, Kseniya ; Schleinitz, Nicolas ; Hatzoglou, Vaios ; Cuibus, M. Adriana ; Bossert, Dana ; Diamond, Eli L. ; Fujino, Takeshi ; Yabe, Mariko ; Shpilberg, Ofer ; Durham, Benjamin H. ; Hautala, Timo ; Witkowski, Matthew ; Rosen, Neal ; Cohen-Aubart, Fleur ; Castro, Cynthia ; Lewis, Alexander M. ; Rösler, Wiebke ; Mazor, Roei D. ; Ulaner, Gary A.

Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1^E102_I103del) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1^E102_I103del-mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses.

2025-09-01·BIOCHEMICAL PHARMACOLOGY

Molecular Dissection of the AHR-AREG driven EGFR-ERK1/2-CyclinD1 axis in acquired lenvatinib resistance of Hepatocellular carcinoma

Article

作者: Wang, Ruilin ; An, Lin ; Diao, Jinmei ; Hu, Yuelei ; Sun, Dawei ; Liu, Juan

Lenvatinib serves as a first-line systemic therapy for advanced hepatocellular carcinoma (HCC), yet the development of resistance poses a major clinical challenge. The purpose of this study is to investigate the mechanisms underlying lenvatinib resistance in HCC and identify potential interventions. We established lenvatinib-resistant HuH7 and Hep3B cell lines and conducted in vitro, bioinformatics, and biochemical assays to explore and validate the mechanisms underlying acquired resistance to lenvatinib in HCC. Additionally, cellular xenograft models of lenvatinib-resistant HCC were utilized to assess tumor responses to a novel drug treatment regimen. Our findings revealed a shift from suppression to activation in the expression of p-ERK1/2 and Cyclin D1 in HCC cells as they transitioned from sensitivity to resistance to lenvatinib. Furthermore, we demonstrated that targeting ERK1/2 with ravoxertinib (an ERK1/2 inhibitor) could significantly enhance the sensitivity of resistant HCC cells to lenvatinib therapy. Through transcriptome data analysis and experimental validation, we identified amphiregulin (AREG), induced autocrinely by lenvatinib, as a critical mediator that activates the EGFR-ERK1/2 signaling pathway, leading to increased Cyclin D1 expression in HCC cells. Mechanistically, lenvatinib promotes aryl hydrocarbon receptor (AHR) nuclear translocation, directly activating AREG transcription. Using in vivo models, we further confirmed that inhibiting ERK1/2 with ravoxertinib or AHR with CH-223191 (an AHR inhibitor) could overcome lenvatinib resistance in HCC. Overall, lenvatinib-induced AHR activation promotes AREG expression, which subsequently facilitates the acquisition of drug resistance in HCC via the EGFR-ERK1/2-CyclinD1 signaling axis. Targeting ERK1/2 and AHR effectively improved the response to lenvatinib treatment in resistant HCC.

项与 ERK1/2 inhibitor (GEn1E Lifesciences) 相关的新闻（医药）

2025-12-10

·EndPoints

D3 Bio raises $108M to take next-gen KRAS G12C drug into Phase 3

D3 Bio has secured $108 million in a Series B fundraise, with the main goal of advancing its lead drug candidate targeting KRAS-G12C into global registrational trials. The Shanghai-based biotech plans to evaluate the drug, called elisrasib, as both a single agent and in combination regimens for several KRAS G12C-mutant cancers, according to a Wednesday release . Elisrasib monotherapy is currently in Phase 2 development for mutated forms of second-line or later non-small cell lung cancer (NSCLC), pancreatic cancer and colorectal cancer. It’s also being tested in separate combination regimens for earlier settings in mutant forms of NSCLC and colorectal cancer. There are two KRAS G12C inhibitors on the US market: Amgen’s Lumakras and Bristol Myers Squibb’s Krazati. Both are approved for mutant forms of NSCLC and colorectal cancer. Wednesday’s raise was backed by new and existing investors, including IDG Capital, SongQing Capital, WuXi AppTec’s Corporate Venture Fund and Medicxi. In April 2024, Medicxi poured $40 million into D3’s Series A+ fundraise, which came to a total of $62 million . At that time, Medicxi said there’s still a demand for new and improved KRAS G12C inhibitors that can boost response rates, duration of response and CNS penetration for patients. According to D3, elisrasib has demonstrated “high covalent potency” and “CNS penetration properties” in preclinical studies. The company also previously shared data from a Phase 1/2 trial of elisrasib in a range of mutant solid tumors, showing an ORR of about 71% and tumor shrinkage in a small number of patients with stable brain metastases. Proceeds from the Series B will also support the development of D3’s broader immuno-oncology pipeline, which includes an ERK1/2 kinase inhibitor called D3S-002 that’s in Phase 1 for solid tumors with a MAPK mutation. The biotech launched in 2020 with $200 million in Series A backing.

临床2期上市批准免疫疗法临床1期临床3期

2025-12-10

·Firstwordpharma

D3 Bio secures $108M series B to give KRAS programme late-stage push

China-based D3 Bio said Tuesday it successfully closed a $108-million series B financing to fund global Phase III testing of its lead KRAS G12C inhibitor elisrasib (D3S-001), and to propel its broader oncology pipeline.The latest round was led by IDG Capital and SongQing Capital, with participation from existing backers WuXi AppTec's Corporate Venture Fund, Temasek, HSG, MPCi, and Medicxi."This funding enables us to advance our lead programme into late-stage clinical trials and further expand our pipeline of innovative therapies designed to benefit patients globally," said George Chen, founder and chief executive of D3 Bio.The company noted proceeds from the megaround will primarily support pivotal trials evaluating the lead asset as monotherapy and in combination regimens for KRAS G12C-mutant cancers — particularly non–small-cell lung cancer, colorectal cancer, and pancreatic cancer — across the US, China and the EU. Elisrasib, which was granted Breakthrough Therapy and Orphan Drug Designations by the FDA earlier this year, is currently undergoing Phase II evaluation for the same.Additional funds will also provide a push to D3 Bio's investigational portfolio of targeted and immuno-oncology programmes with first-in-class or best-in-class potential, which includes D3S-002, a "distinctively designed" ERK1/2 kinase inhibitor in early-stage clinical testing for solid tumours.Launched in 2020 with $200 million, the biotech bagged a $40-million investment from Medicxi last year as part of a larger $62-million series A+ fundraise.

临床2期孤儿药突破性疗法临床申请

2025-04-24

·FierceBiotech

Mosaic adds to cancer combo pattern by licensing 2 clinical-stage drugs from Astex

In return for the licenses, Astex will receive 19% of Mosaic Therapeutics’ equity, with a further 3% to follow if milestones are hit.\n Mosaic Therapeutics has secured the latest pieces in its combination medicine strategy by licensing two clinical stage tumor drugs from fellow British biotech Astex Pharmaceuticals.The small molecules in question are ASTX029, an ERK1/2 inhibitor that has completed a phase 2 study, and ASTX295 an MDM2 antagonist that has undergone a phase 1 trial. Both candidates have demonstrated “single-agent activity as monotherapies, enabling use in combination therapies,” Mosaic explained in an April 24 release.In return for the licenses, Astex—which is owned by Otsuka Pharmaceutical—will receive 19% of Mosaic’s equity, with a further 3% to follow if milestones are hit.Cambridge, U.K.-based Mosaic secured a $28 million series A two years ago to fund its ambition to “resolve cancer’s complexity to power new treatments for patients.” In practice, this means combing through large datasets to identify combinations of oncology drugs that could increase their effectiveness in biomarker-defined patient populations.This morning’s deal “significantly accelerates Mosaic’s development path,” the biotech\'s chair Edward Hodgkin said in the April 24 release, meaning the company now expects to launch its first clinical study of a combination treatment next year. “The in-licensing of these two clinical stage assets provides a step change in our development pipeline, allowing Mosaic to progress targeted drug combinations in novel biomarker-defined settings and enabling the delivery of precision medicines for patients who currently have few therapeutic options,” added Hodgkin, who is also managing partner of Mosaic’s backer Syncona Investment Management.Astex, which like Mosaic is based in Cambridge in England, has a strong track record of working with Big Pharma in the past, including collaborating with the Novartis Institutes for BioMedical Research on breast cancer med Kisqali and AstraZeneca on its breast cancer treatment Truqap in the mid-2000s. More recently, the biotech secured a 2023 deal with Merck & Co.“We recognise the significance of Mosaic’s platform, which has identified these two assets as anchor components of a pipeline of potential combination products,” Astex’s CEO and co-founder Harren Jhoti, Ph.D., said in the release. “Both drug targets are well-characterised drivers of many cancers, and we are excited to be working with the experienced team at Mosaic to expand the Company’s pipeline in combination therapies with high unmet medical need.”