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

Rákkutatás · NSCLC · BRAF

Exarafenib is a pan-RAF inhibitor that shows potent activity against BRAF Class II and III mutations in non‑small cell lung cancer (NSCLC) and overcomes resistance through ARAF‑KSR1 complex formation, suggesting effective combination strategies.

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.

BRAF mutations in NSCLC are a significant unmet clinical need, especially for Class II/III variants which lack effective targeted therapies. Exarafenib offers a new therapeutic option for these patients and provides insight into resistance mechanisms, enabling rational combination treatments to improve outcomes.

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