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Molecular Mechanism Underlying Paradoxical Oncogenic Effect of BRAF Inhibitor Treatment
Author(s) -
Wang Zhihong,
Candelora Christine,
Cope Nicholas,
Wong Kenneth
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb97
Subject(s) - melanoma , kinase , cancer research , phosphorylation , serine , protein kinase domain , mechanism (biology) , mapk/erk pathway , protein kinase a , biology , medicine , pharmacology , genetics , mutant , gene , philosophy , epistemology
The serine/threonine kinase, BRAF, is a known driver of melanoma progression and is somatically mutated in 40–60% of melanomas. Inhibitors targeting the ATP binding site of the catalytic domain of BRAF provide significant short‐term clinical benefits in the majority of melanoma patients. Surprisingly, those ATP competitive inhibitors paradoxically activate downstream signaling in melanoma patients bearing wild‐type BRAF. The unexpected consequence of inhibitor‐stimulated growth of certain cancers casts doubt on anti‐BRAF therapy. Thus, alternative BRAF‐targeted therapies are urgently needed and are likely to emerge from a better understanding of the extremely complex regulation mechanisms of the BRAF kinase. In order to identify the regulatory factors that lead to drug paradoxical effects, we characterize the purified full‐length RAF family kinases, in particular BRAF and CRAF. Our preliminary data demonstrate that full‐length BRAF recapitulates the paradoxical effect in vitro . Further biochemical studies were conducted to investigate how phosphorylation and protein‐protein interaction impact BRAF regulation and drug sensitivity. Support or Funding Information USciences Startup