title: Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin.
abstract: The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies.
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Marcia R
authors: MR
authors: Campbell
authors: Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1708, San Francisco, CA, 94143, USA.
authors: Hui
authors: H
authors: Zhang
authors: Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1708, San Francisco, CA, 94143, USA.
authors: Shabnam
authors: S
authors: Ziaee
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Ana
authors: A
authors: Ruiz-Saenz
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Nathaniel
authors: N
authors: Gulizia
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Julie
authors: J
authors: Oeffinger
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Dhara N
authors: DN
authors: Amin
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
authors: Deepika
authors: D
authors: Ahuja
authors: Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA. mark.moasser@ucsf.edu.
authors: Mark M
authors: MM
authors: Moasser
authors: Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1708, San Francisco, CA, 94143, USA. catherine.park@ucsf.edu.
authors: Catherine C
authors: CC
authors: Park
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004318:Doxycycline / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000187:drug effects / Q000235:genetics*; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D004318:Doxycycline; D019012:Integrin beta1; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3
keywords: AIIB2; Combination therapy; HER2; HER3; OS2966; β1 integrin