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Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.

Foster SA, Whalen DM, Özen A, Wongchenko MJ, Yin J, Yen I, Schaefer G, Mayfield JD, Chmielecki J, Stephens PJ, Albacker LA, Yan Y, Song K, Hatzivassiliou G, Eigenbrot C, Yu C, Shaw AS, Manning G, Skelton NJ, Hymowitz SG, Malek S
Cancer Cell 29 477-493 (2016)
Related entries: 5hi2, 5hib, 5hid, 5hie

Cited: 108 times
EuropePMC logo PMID: 26996308

Abstract

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

Articles - 5hic mentioned but not cited (1)

  1. Molecular Docking Optimization in the Context of Multi-Drug Resistant and Sensitive EGFR Mutants. García-Godoy MJ, López-Camacho E, García-Nieto J, Nebro AJ, Aldana-Montes JF. Molecules 21 E1575 (2016)


Reviews citing this publication (32)

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Articles citing this publication (75)

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