Pathways and targeting avenues of BRAF in non-small cell lung cancer

ABSTRACT

Introduction

BRAF is a serine-threonine kinase implicated in the regulation of MAPK signaling cascade. BRAF mutation-driven activation occurs in approximately 2–4% of treatment-naive non-small cell carcinomas (NSCLCs). BRAF upregulation is also often observed in tumors with acquired resistance to receptor tyrosine kinase inhibitors (TKIs).

Areas covered

This review describes the spectrum of BRAF mutations and their functional roles, discusses treatment options available for BRAF p.V600 and non-V600 mutated NSCLCs, and identifies some gaps in the current knowledge.

Expert opinion

Administration of combined BRAF/MEK inhibitors usually produces significant, although often a short-term, benefit to NSCLC patients with BRAF V600 (class 1) mutations. There are no established treatments for BRAF class 2 (L597, K601, G464, G469A/V/R/S, fusions, etc.) and class 3 (D594, G596, G466, etc.) mutants, which account for up to two-thirds of BRAF-driven NSCLCs. Many important issues related to the use of immune therapy for the management of BRAF-mutated NSCLC deserve further investigation. The rare occurrence of BRAF mutations in NSCLC is compensated by high overall incidence of lung cancer disease; therefore, clinical studies on BRAF-associated NSCLC are feasible.

GRAPHICAL ABSTRACT

KEYWORDS:

• BRAF
• mutation
• non-small cell lung cancer
• targeted therapy
• immunotherapy
• acquired resistance

Article highlights

• BRAF mutations account for 2–4% of treatment-naive non-small cell lung carcinomas (NSCLCs).

• BRAF exon 15 p.V600 substitutions occur in 1–2% of NSCLCs and can be targeted by combined BRAF/MEK inhibition.

• No validated treatment options exist for BRAF non-V600 mutated NSCLCs.

• Important issues still need to be addressed in relation to the use of immune therapy in BRAF-driven NSCLCs.

• Some treatment schemes, with proven efficacy in BRAF-mutated melanomas and colorectal cancers, deserve to be studied in NSCLC.

Abbreviations

ICI	=	immune checkpoint inhibitor
MAPK	=	mitogen-activated protein kinase
NGS	=	next generation sequencing
NSCLC	=	non-small cell lung cancer
OS	=	overall survival
TKI	=	tyrosine kinase inhibitor
TMB	=	tumor mutation burden

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We are cordially thankful to William R. Miller (University of Edinburgh, UK) for his invaluable help in improving this manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2024.2374742.

Additional information

Funding

This study has been supported by the Russian Science Foundation [grant number 24-45-10014].