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

Scott A Foster; Daniel M Whalen; Ayşegül Özen; Matthew J Wongchenko; JianPing Yin; Ivana Yen; Gabriele Schaefer; John D Mayfield; Juliann Chmielecki; Philip J Stephens; Lee A Albacker; Yibing Yan; Kyung Song; Georgia Hatzivassiliou; Charles Eigenbrot; Christine Yu; Andrey S Shaw; Gerard Manning; Nicholas J Skelton; Sarah G Hymowitz; Shiva Malek

doi:10.1016/j.ccell.2016.02.010

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

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

Authors

Scott A Foster¹, Daniel M Whalen², Ayşegül Özen³, Matthew J Wongchenko⁴, JianPing Yin², Ivana Yen¹, Gabriele Schaefer⁵, John D Mayfield⁶, Juliann Chmielecki⁶, Philip J Stephens⁶, Lee A Albacker⁶, Yibing Yan⁴, Kyung Song⁵, Georgia Hatzivassiliou⁷, Charles Eigenbrot², Christine Yu², Andrey S Shaw¹, Gerard Manning⁸, Nicholas J Skelton⁹, Sarah G Hymowitz², Shiva Malek¹⁰

Affiliations

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: [email protected].

PMID: 26996308
DOI: 10.1016/j.ccell.2016.02.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amino Acid Substitution
Antineoplastic Agents / pharmacology
Base Pairing / genetics
Conserved Sequence
Dimerization
Drug Resistance, Neoplasm / genetics
Enzyme Activation / genetics
ErbB Receptors / metabolism
Genes, erbB-1*
Genes, erbB-2*
Humans
Models, Molecular
Molecular Sequence Data
Mutation*
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Neoplasms / enzymology
Neoplasms / genetics*
Protein Conformation
Protein Interaction Mapping
Protein Kinase Inhibitors / pharmacology
Protein Structure, Secondary
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics*
Proto-Oncogene Proteins B-raf / metabolism
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Structure-Activity Relationship

Substances

Antineoplastic Agents
Neoplasm Proteins
Protein Kinase Inhibitors
EGFR protein, human
ERBB2 protein, human
ErbB Receptors
Receptor, ErbB-2
BRAF protein, human
Proto-Oncogene Proteins B-raf