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Cancer Cell. 2016 Apr 11;29(4):477-493. doi: 10.1016/j.ccell.2016.02.010. Epub 2016 Mar 17.

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

Author information

1
Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2
Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Oncology Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
5
Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
6
Foundation Medicine, 150 Second Street, Cambridge, MA 02141, USA.
7
Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
8
Department of Bioinformatics & Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
9
Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
10
Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: shivam@gene.com.

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.

PMID:
26996308
DOI:
10.1016/j.ccell.2016.02.010
[Indexed for MEDLINE]
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