Tadashi Manabe, Hannah C. Bergo, Qingtian Li, Tim Sen Wang, Paul Severson, Nichol Miller, Catherine Lee, Elifnur Yay Donderici, Nicole Zhang, Wei Wu, Yu-Ting Chou, D. Lucas Kerr, Paul Allegakoen, Kathryn B. Grandinetti, Liliana Soroceanu, Robert J. Pelham, Eric S. Martin, Eric A. Murphy, Vishesh Khanna, Joel Neal, Christopher T Chen, Shumei Kato, R. Williams, Trever G. Bivona
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.