BRAF Targeting Across Solid Tumors: Molecular Aspects and Clinical Applications

Abstract

BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer's tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics.

Keywords: BRAF; molecular oncology; precision oncology; targeted therapy; tissue specificity.

Figure 1

Mechanism of action of anti-BRAF/MEK drugs on the RAS signaling pathway. RTK, receptor tyrosine kinase (including vegFR, PDGFR, and EGFR); RAS, rat sarcoma virus protein; BRAF, v-Raf murine sarcoma viral oncogene homolog B (including BRAF, CRAF, and ARAF); BRAF V600E, a common activating mutation in BRAF; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase. Figure made with BioRender.

Figure 2

ORR, PFS, and OS in selected trials of BRAF-MEK inhibition in adult solid cancers. BTC, biliary tract cancer; ATC, anaplastic thyroid carcinoma; NSCLC, non-small-cell lung cancer; HGG, high-grade glioma (results for low grade glioma are incomplete). ORR, objective response rate; mPFS, median progression-free survival; mOS, median overall survival. Figure made with BioRender.