Abstract

BRAF is mutated at a high frequency in various malignancies, including melanoma, papillary thyroid carcinoma and colorectal adenocarcinoma. BRAF is an element of the RAS/RAF/MEK/ERK (MAPK) pathway, which when constitutively active can lead to increased proliferation rate, enhanced survival, invasion and metastasis. The development of small molecule inhibitors of mutant BRAF kinase has changed the care of patients, especially with melanoma. Despite the success in treating melanoma with inhibitors of mutant BRAF and other elements of RAS/RAF/MEK/ERK (MAPK) pathway, resistance limits the long-term responsiveness to these drugs. The resistance mechanisms to MAPK pathway inhibition are complex, occur at genomic and phenotypic levels, and frequently the same patient can simultaneously develop diverse mechanisms of resistance in different progressive metastases or even in the same lesion. In the current review, we summarize recent research on mutations in BRAF and their importance for the development of tumor. This review will also give an overview on the current knowledge concerning therapies for patients harboring mutation in BRAF and discusses the diverse mechanisms of resistance developed in response to these targeted therapies.

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