| Title: |
Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies |
| Authors: |
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; Daniel L. Kerr; Paul Allegakoen; Kathryn B. Grandinetti; Liliana Soroceanu; Robert J. Pelham; Eric S. Martin; Eric A. Murphy; Vishesh Khanna; Joel W. Neal; Christopher T. Chen; Shumei Kato; Richard Williams; Trever G. Bivona |
| Source: |
Nature Communications, Vol 17, Iss 1 (2026) |
| Publisher Information: |
Nature Portfolio, 2026. |
| Publication Year: |
2026 |
| Collection: |
LCC:Science |
| Subject Terms: |
Science |
| Description: |
Abstract 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. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://doaj.org/toc/2041-1723 |
| DOI: |
10.1038/s41467-026-69216-3 |
| Access URL: |
https://doaj.org/article/cd6a4fe54ffd4ff2b507149fd92f695e |
| Accession Number: |
edsdoj.6a4fe54ffd4ff2b507149fd92f695e |
| Database: |
Directory of Open Access Journals |