AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest T. Yamada received commercial research grants from Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and has received speaking honoraria from Eli Lilly. H. Kawachi received personal fees from Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan KK, and MSD KK, outside the purview of the submitted work. N. Furuya received personal fees from AstraZeneca, Chugai, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Taiho, and Novartis. S. Watanabe received grants and personal fees from Boehringer Ingelheim and Nippon Kayaku. Personal fees from Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical. S. Yano received research grants from Chugai Pharmaceutical and Boehringer-Ingelheim and has received speaking honoraria from Amgen, Chugai Pharmaceutical, Boehringer-Ingelheim, Novartis, and Pfizer. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical and Oncolys BioPharma, and a patent fee from JT Pharmaceutical. K. Takayama reports receiving research grants from Chugai-Roche Co., and Ono Pharmaceutical Co., and personal fees from AstraZeneca Co., Chugai-Roche Co., MSD-Merck Co., Eli Lilly Co., Boehringer-Ingelheim Co., and Daiichi-Sankyo Co.No potential conflicts of interest were disclosed by the other authors.