title: Targeting BRAF mutant metastatic colorectal cancer: clinical implications and emerging therapeutic strategies.
abstract: Increasing knowledge of the underlying signaling pathways and molecular defects involved in colorectal cancer growth or progression enabled the discovery of several prognostic and predictive biomarkers, leading to the development of novel molecularly targeted therapies. The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10 % of colorectal cancer and play a clear pathogenic role, particularly in patients with metastatic disease. Intense efforts have therefore focused on targeting BRAF as an oncogenic driver, with mixed early results. This article summarizes the molecular and clinical features of BRAF mutant colorectal cancer, the prognostic and predictive role of BRAFV600E mutation in colorectal cancer, initial clinical trial results in targeting BRAFV600E, and the more recent preclinical insights into potential mechanisms of resistance to BRAF inhibition that have now led to a number of rationale-driven combination therapeutic strategies.
authors.affiliation: Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, VIC, Australia.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tie
authors.forename: Jayesh
authors.initials: J
authors.lastname: Desai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf