New Treatment Strategy and Future Research Direction for BRAF-Mutated Cancer.

BRAF is a key oncogene in various malignancies including malignant melanoma, thyroid cancer, colorectal cancer, and lung cancer. The protein it encodes is a constituent of the mitogen-activated protein kinase pathway that regulates cell growth. Mutations, mainly BRAFV600E, that cause the activation of BRAF in turn induce MEK and ERK activation through their phosphorylation, which promotes the growth and survival of cancer cells. Treatment with BRAF inhibitor, and more recently, treatment with BRAF inhibitor plus MEK inhibitor was first developed in malignant melanoma.

In 2022, treatment with BRAF inhibitor plus MEK inhibitor was approved tumor-agnostically for the treatment of BRAFV600E-mutated cancer, apart from colorectal cancer, in the USA. In colorectal cancer, the combination of a BRAF inhibitor and an anti-EGFR antibody was developed in a later line setting, and more recently, the combination of a BRAF inhibitor, an anti-EGFR antibody and chemotherapy was developed. Despite the recent advances of BRAF-targeted therapies, intrinsic and/or acquired resistance to those therapies still needs to be overcome. We discuss the current status of the clinical development of BRAF-targeted therapy, clinical findings on the resistance mechanism, and new possible treatment strategies for patients with BRAF-mutated cancer.