title: Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum.
abstract: There is increasing evidence implicating human epidermal growth factor receptor 3 (HER3) in several types of cancer. However, the development of targeted therapies to inactivate HER3 function has been a challenging endeavor. Its kinase domain functions in allostery not catalysis, and the classical ATP-analog class of tyrosine kinase inhibitors fail to inactivate it. Here we describe a novel approach that eliminates HER3 expression. The small-molecule cotransin CT8 binds the Sec61 translocon and prevents the signal peptide of the nascent HER3 protein from initiating its cotranslational translocation, resulting in the degradation of HER3 but not the other HER proteins. CT8 treatment suppresses the induction of HER3 that accompanies lapatinib treatment of HER2-amplified cancers and synergistically enhances the apoptotic effects of lapatinib. The target selectivities of cotransins are highly dependent on their structure and the signal sequence of targeted proteins and can be narrowed through structure-function studies. Targeting Sec61-dependent processing identifies a novel strategy to eliminate HER3 function.
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ruiz-Saenz
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sandhu
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Carrasco
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Maglathlin
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.|Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Taunton
authors.affiliation: Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Moasser
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014176:Protein Biosynthesis; D021381:Protein Transport; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069816:SEC Translocation Channels
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D000069816:SEC Translocation Channels; C502316:cotransin; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3