title: Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.
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.
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Foster
authors.affiliation: Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Whalen
authors.affiliation: 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.
authors.forename: Ayşegül
authors.initials: A
authors.lastname: Özen
authors.affiliation: Department of Oncology Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wongchenko
authors.affiliation: Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: JianPing
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA 02141, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Mayfield
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA 02141, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA 02141, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, 150 Second Street, Cambridge, MA 02141, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Albacker
authors.affiliation: Department of Oncology Biomarker Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Cancer Immunology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.affiliation: Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.affiliation: Department of Bioinformatics & Computational Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.affiliation: Department of Protein Chemistry & Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Hymowitz
authors.affiliation: Department of Discovery Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: shivam@gene.com.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology; D020029:Base Pairing / Q000235:genetics; D017124:Conserved Sequence; D019281:Dimerization; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017433:Protein Structure, Secondary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human