Small- molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS- mutant cancers

• 成果类型: Article
• 署名作者: Jansen, Robin A.; Mainardi, Sara; Dias, Matheus Henrique; Bosma, Astrid; van Dijk, Emma; Selig, Roland; Albrecht, Wolfgang; Laufer, Stefan A.; Zender, Lars; Bernards, Rene
• 署名单位: Netherlands Cancer Institute; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; Eberhard Karls University Hospital; Helmholtz Association; German Cancer Research Center (DKFZ)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13287
• DOI: 10.1073/pnas.2319492121
• 发表日期: 2024-02-27
• 关键词: colon-cancer; lung-cancer; kinase; activation; resistance

摘要

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRASG12C and pan-RAS inhibitors in KRAS-mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well- tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS- driven cancers.