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Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies
期刊文章

Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies

T. Manabe, H.C. Bergo, Q. Li, T.S. Wang, P. Severson, N. Miller, C. Lee, E. Yay Donderici, N. Zhang, W. Wu, …
Nature Communications, 卷.17(1)
2026
DOI: https://doi.org/10.1038/s41467-026-69216-3
Web of Science ID: WOS:001716580900003

摘要

Animals Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Drug Resistance, Neoplasm Female Humans Lung Neoplasms Mice Mutation Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Xenograft Model Antitumor Assays antineoplastic agent B Raf kinase belvarafenib beroterkib binimetinib carboplatin circulating tumor DNA cisplatin dabrafenib daraxonrasib encorafenib exarafenib ipatasertib mitogen activated protein kinase naporafenib pembrolizumab pemetrexed protein protein araf protein ksr1 Ras protein rmc 4550 sotorasib trametinib unclassified drug vemurafenib B Raf kinase BRAF protein, human protein kinase inhibitor cancer cell component database inhibition inhibitor mutation signaling tumor acne aged animal experiment animal model antineoplastic activity Article cancer chemotherapy cancer patient cancer resistance clinical article clinical feature clinical trial combination drug therapy controlled study dermatitis disease classification dose response drug dose reduction drug efficacy enzyme activity enzyme inhibition female first-line treatment gene mutation genomics human in vitro study in vivo study maintenance therapy male MAPK signaling monotherapy mouse multiple cycle treatment non small cell lung cancer nonhuman prevalence rash treatment outcome animal drug effect drug resistance drug screening drug therapy genetics lung tumor metabolism mutation non small cell lung cancer pathology tumor cell line
Oncogenic BRAF mutations, including those in non-small cell lung cancer (NSCLC), are classified as Class I, II, or III. While approved therapies exist for BRAF Class I mutants, no approved therapies exist for Class II and III BRAF-mutated NSCLC. Analysis of a circulating tumor DNA database reveals Class II and III mutations comprise ~65% of BRAF-mutant NSCLC cases, with Class II patients showing worse outcomes than Class I. Exarafenib, a distinct pan-RAF inhibitor, demonstrates potent activity against BRAF Class II and III mutant preclinical models and initial clinical activity. Resistance studies reveal rewiring to an ARAF-mediated bypass pathway, characterized by RAS-mediated ARAF-KSR1 complexes maintaining MAPK signaling despite pan-RAF inhibitor treatment. RAS or MEK inhibition co-targeting is effective against this resistance mechanism. This study provides preclinical rationale for clinical testing of exarafenib in BRAF Class II/III cancers and unveils RAS-mediated ARAF-KSR1 complex formation as a resistance mechanism and rational co-therapy strategies. © The Author(s) 2026.

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