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

## TL;DR

A new drug called exarafenib shows promise for treating a common type of lung cancer with specific BRAF mutations and identifies a resistance mechanism.

## Contribution

Exarafenib's effectiveness against BRAF Class II/III NSCLC and the discovery of ARAF-KSR1 resistance mechanism and combination strategies.

## Key findings

- Exarafenib demonstrates potent activity against BRAF Class II and III mutant preclinical models.
- Resistance to exarafenib involves RAS-mediated ARAF-KSR1 complexes maintaining MAPK signaling.
- Combining exarafenib with RAS or MEK inhibitors can overcome resistance.

## 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.

While therapies targeting type I BRAF mutations have been developed, there are limited options for those with type II and III mutations. Here, the authors identify a subset of BRAF-mutant non-small cell lung cancer patients and characterise the pan-RAF inhibitor exarafenib, demonstrating efficacy in preclinical models and investigating subsequent resistance mechanisms.