Role of mitochondria and potential of mitochondria-targeted therapy in BRAF mutant cancer: A review

The classical mitogen-activated protein kinase (MAPK) signaling pathway, the Ras/Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK protein kinase cascade, is a conserved cascade that regulates cell growth, differentiation, and proliferation. The significance of BRAF in cancer was established with the discovery of cancer-activating mutations in BRAF in several human tumors in 2002. Currently, BRAF is recognized as a driver mutation that affects cancer phenotypes in different ways, making it an important therapeutic target for cancer. BRAF-selective inhibitors have shown promise in clinical trials involving patients with metastatic melanoma. However, resistance mechanisms to BRAF inhibitors therapy have resulted in short-lived therapeutic responses. Further in-depth research is imperative to explore resistance mechanisms that oppose the effectiveness of BRAF inhibitors. Metabolic reprogramming has emerging role in BRAF-mutant cancers. In particular, mitochondrial metabolism and its closely related signaling pathways mediated by mitochondria have become recognized as potential new targets for treating BRAF-mutant cancers. This review, examines the progress in understanding BRAF mutations in cancer, the clinicopathological correlation of BRAF inhibitors, and recent advances in mitochondrial metabolism, mitochondrial dynamics and mitochondrial mediated death in BRAF-mutant cancer. This review will inform future cancer research and lay the foundation for novel treatment combinations of BRAF-mutant cancers.