Abstract
The RAS–RAF–MEK–ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50–80% of BRAF mutations in non-small cell lung cancer and 22–30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient’s tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.
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Acknowledgements
We thank members of the Siegel and Watson laboratories for their critical comments on the manuscript.
Funding
MD acknowledges MD/PhD training support from the Canadian Institutes of Health Research (CIHR) and the Brain Tumor Foundation of Canada. AANR acknowledges receipt of a David Cornfield Melanoma Fund Award. PMS acknowledges research support from the US Department of Defense (US DOD - CA140389), IRW is funded by grants from the Melanoma Research Alliance (MRA – Grant #412429), the V Foundation (Grant #V2016–023), and the Canadian Institute of Health Research (CIHR – Grant # PJT-152975). PMS is a William Dawson Scholar of McGill University and IRW is a Canada Research Chair.
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These authors contributed equally: Matthew Dankner and April A.N. Rose.
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Dankner, M., Rose, A.A.N., Rajkumar, S. et al. Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene 37, 3183–3199 (2018). https://doi.org/10.1038/s41388-018-0171-x
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DOI: https://doi.org/10.1038/s41388-018-0171-x
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