title: Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.
abstract: BACKGROUND
  Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.
  
  
  METHODS
  A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease.
  
  
  RESULTS
  Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer.
  
  
  CONCLUSIONS
  Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.
authors.affiliation: Department of Medical Oncology, Beaumont Hospital, Dublin; Our Lady of Lourdes Hospital, Drogheda.
authors.forename: M S N
authors.initials: MSN
authors.lastname: Mohd Sharial
authors.affiliation: Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Crown
authors.affiliation: Department of Medical Oncology, Beaumont Hospital, Dublin; Our Lady of Lourdes Hospital, Drogheda. Electronic address: bryanhennessy74@gmail.com.
authors.forename: B T
authors.initials: BT
authors.lastname: Hennessy
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068338:Everolimus; D007166:Immunosuppressive Agents; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C546842:MTOR protein, human; C508053:ERBB2 protein, human