title: Co-targeting the HER and IGF/insulin receptor axis in breast cancer, with triple targeting with endocrine therapy for hormone-sensitive disease.
abstract: OBJECTIVE
  Interactions between HER2, estrogen receptor (ER), and insulin-like growth factor I receptor (IGF1R) are implicated in resistance to monotherapies targeting these receptors. We have previously shown in pre-clinical studies synergistic anti-tumor effects for co-targeting each pairwise combination of HER2, IGF1R, and ER. Strikingly, synergy for HER2/IGF1R targeting occurred not only in a HER2+ model, but also in a HER2-normal model. The purpose of the current study was therefore to determine the generalizability of synergistic anti-tumor effects of co-targeting HER2/IGF1R, the anti-tumor activity of triple-targeting HER2/IGF1R/ER in hormone-dependent cell lines, and the effect of using the multi-targeting drugs neratinib (pan-HER) and BMS-754807 (dual IGF1R/insulin receptor).
  
  
  METHODS
  Proliferation and apoptosis assays were performed in a large panel of cell lines representing varying receptor expression levels. Mechanistic effects were studied using phospho-protein immunoblotting. Analyses of drug interaction effects were performed using linear mixed-effects regression models.
  
  
  RESULTS
  Enhanced anti-proliferative effects of HER/IGF-insulin co-targeting were seen in most, though not all, cell lines, including HER2-normal lines. For ER+ lines, triple targeting with inclusion of anti-estrogen generally resulted in the greatest anti-tumor effects. Double or triple targeting generally resulted in marked increases in apoptosis in the sensitive lines. Mechanistic studies demonstrated that the synergy between drugs was correlated with maximal inhibition of Akt and ERK pathway signaling.
  
  
  CONCLUSIONS
  Dual HER/IGF-insulin targeting, and triple targeting with inclusion of anti-estrogen drugs, shows striking anti-tumor activity across breast cancer types, and drugs with broader receptor specificity may be more effective than single receptor selective drugs, particularly for ER- cells.
authors.affiliation: Section of Medical Oncology, Departments of Internal Medicine, Yale Cancer Center, Smilow Cancer Hospital, Yale University School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06510, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Section of Medical Oncology, Departments of Internal Medicine, Yale Cancer Center, Smilow Cancer Hospital, Yale University School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06510, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Hatzis
authors.affiliation: Section of Medical Oncology, Departments of Internal Medicine, Yale Cancer Center, Smilow Cancer Hospital, Yale University School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06510, USA. michael.digiovanna@yale.edu.
authors.forename: Michael P
authors.identifier: http://orcid.org/0000-0002-4902-3196
authors.initials: MP
authors.lastname: DiGiovanna
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068878:Trastuzumab / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D011720:Pyrazoles; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D013629:Tamoxifen; D000068878:Trastuzumab; D014227:Triazines; C545990:BMS 754807; C000597236:IGF1R protein, human; C016601:afimoxifene; C508053:ERBB2 protein, human; C487932:neratinib; C525021:figitumumab
keywords: Breast cancer; Estrogen receptor (ER); HER2; Insulin-like growth factor (IGF); Neratinib; Trastuzumab