HER receptor signaling confers resistance to IGF-1R targeted therapy

Abstract

14510 Background: Signaling through the insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the resistance to a number of clinically relevant anti-cancer agents, including inhibitors of the HER family of receptors. Preliminary data suggests that co-inhibition of IGF and HER pathways may improve the efficacy of targeting these pathways individually. Methods: Five ovarian cancer cell line where treated with the IGF-1R inhibitor, BMS-536924 (924) and/or the panHER inhibitor, BMS-599626. Activity was assessed by proliferation and apoptotic assays. Protein expression/activation was assessed by western blotting. Stably transfected MCF-7 variants were generated to contain either the empty expression vector (M/-), EGFR/HER1 (M/H1) or HER2 (M/H2). MCF-7R4 cells (R4) are a clonal isolate of MCF-7 cells passaged in high concentration of the IGF-1R inhibitor, BMS-554417. The expression profile of R4 cells were compared to MCF-7 using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Results: IGF-1R and HER receptor co-inhibition had synergistic anti- proliferative activity in all 5 ovarian cell lines investigated. The mechanism of this synergy was enhancement of apoptosis. Evidence of HER receptor activation was observed in all cell lines in response to IGF-1R inhibition. M/H1 and M/H2 became highly resistant to the effects of 924 in the presence of EGF and heregulin, respectively. R4 cells are cross-resistant to 924 and other IGF-1R inhibitors. Compared to MCF-7 cells, HER2 and HER3 are upregulated and overactivated in R4 cells. Additionally, R4 cells have altered expression of IGFBP-5, -6 and IRS-1, -2. Conclusions: Co-inhibition of IGF-1R and HER receptors leads to synergistic activity in all tested ovarian cancer cell lines, all of which exhibited evidence of crosstalk. Activated EGFR or HER2 appears sufficient for resistance to IGF-1R inhibition. As IGF-1R inhibition strategies enter the clinic, HER receptors status and consideration of co-inhibition will be important for their development. Several IGF-1 system related proteins, including IGFBP-5 and 6 may have utility in predicting response to IGF-1R targeted therapy. Supported by the ASCO Young Investigator Award, Mayo Clinic Breast SPORE (CA116201–01) and K12 program (CA090628–05). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, Pfizer Oncology Bristol-Myers Squibb