title: Oncogenic ERBB3 mutations in human cancers.
abstract: The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo.
authors.affiliation: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Bijay S
authors.initials: BS
authors.lastname: Jaiswal
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Chaitali
authors.initials: C
authors.lastname: Parikh
authors.forename: Steffen
authors.initials: S
authors.lastname: Durinck
authors.forename: Subhra
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Joseph
authors.initials: J
authors.lastname: Guillory
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Edgar
authors.forename: Vasantharajan
authors.initials: V
authors.lastname: Janakiraman
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Scholz
authors.forename: Krista K
authors.initials: KK
authors.lastname: Bowman
authors.forename: Maria
authors.initials: M
authors.lastname: Lorenzo
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.forename: Brock A
authors.initials: BA
authors.lastname: Peters
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Kan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Michelle
authors.initials: M
authors.lastname: Mak
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Merchant
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics*
chemical_list: C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3