title: Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.
abstract: BACKGROUND
  Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment.
  
  
  METHODS
  We devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform.
  
  
  RESULTS
  We found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo.
  
  
  CONCLUSIONS
  This is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients.
authors: Xiu-Rong
authors: XR
authors: Ren
authors: Jiangbo
authors: J
authors: Wang
authors: Takuya
authors: T
authors: Osada
authors: Robert A
authors: RA
authors: Mook
authors: Michael A
authors: MA
authors: Morse
authors: Larry S
authors: LS
authors: Barak
authors: Herbert Kim
authors: HK
authors: Lyerly
authors: Wei
authors: W
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D020880:Neuregulins / Q000378:metabolism / Q000494:pharmacology; D010480:Perhexiline / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020880:Neuregulins; D020893:Receptor, ErbB-3; D010480:Perhexiline