Same mutation, different fates: The Yin-Yang of BRAF-driven therapeutic responses in melanoma and colorectal cancer

BRAF mutations are key oncogenic drivers across multiple cancers, yet their therapeutic exploitation varies markedly by tumor type. In melanoma, the combination of BRAF and MEK inhibitors has revolutionized treatment, yielding unprecedented clinical benefits. However, both intrinsic and acquired resistance mechanisms continue to limit long-term efficacy. In contrast, BRAF-targeted therapies in colorectal cancer (CRC) have shown limited success, even when combined with EGFR inhibitors to counteract compensatory survival pathways. Despite these differences, resistance ultimately emerges in both malignancies, driven by partially overlapping mechanisms that remain incompletely understood in CRC. This review dissects the "yin-yang" of BRAF as a therapeutic vulnerability in these two malignancies, we underscore the critical importance of tumor-specific context in precision oncology. Understanding the divergent responses to BRAF inhibition across cancer types is essential to refine current approaches and guide the development of more effective, personalized treatment strategies.