Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance

Abstract

Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

Keywords: BRAF non-v600; NSCLC; immunotherapy; resistant mechanisms.

Figure 1

BRAF pathway with the most recognized resistance mechanism highlighted. Red arrows indicate the main signaling chain. GOF—gain of function; LOF—loss of function; EGFR—Epidermal Growth Factor Receptor; RTKs—Receptor Tyrosine Kinases; GRB2—Growth Factor Receptor-Bound Protein 2; SHP—Src Homology Phosphatases; GEFs—Guanine nucleotide Exchange Factors; RAS—Rat Sarcoma; NF1—Neurofibromin 1; RAF—Rapidly Accelerated Fibrosarcoma; MEK—Mitogen-Activated Protein Kinase; ERK—Extracellular Signal-Regulated Kinase; PI3K—Phosphoinositide 3-Kinase; AKT—Protein Kinase B; PTEN—Phosphatase and Tensin Homolog; MLK1—Mixed-Lineage Kinase 1; FGF1—Fibroblast Growth Factor 1; FGFR—Fibroblast Growth Factor Receptor; COT—Cot/Tpl2; YAP—Yes-Associated Protein; STATs—Signal Transducer and Activator of Transcription; cMYC—Cellular MYC; ELK1—ETS-Like Protein 1; NF-kB—Nuclear Factor kappa B; RSK—Ribosomal S6 Kinase; AP-1—Activator Protein 1; CDK2NA—Cyclin-Dependent Kinase Inhibitor 2A; MAP2K—Mitogen-Activated Protein Kinase Kinase; CCND1—Cyclin D1; RAC1—Ras-Related C3 Botulinum Toxin Substrate 1.