Abstract A151: Differential mechanisms of acquired resistance to IGF-1R antibody therapy and a small molecule inhibitor, BMS-754807 in a human rhabdomyosarcoma Rh41 model

Abstract

Abstract Background: Overexpression and/or overactivation of IGF-1R have been linked to a number of cancer types including, colon, breast, prostate, lung and sarcoma. These findings support IGF-1R as a promising therapeutic target. Agents targeting IGF-1R, including IGF-1R antibodies and small molecule inhibitors are currently in clinical development. A common phenomenon resulting in clinical failures is the development of resistance to anti-cancer therapies. In the present study, the goal is to compare the mechanisms of acquired resistance to mAb391, an IGF-1R-blocking antibody and to BMS-754807, a small molecule dual inhibitor targeting IGF-1R/IR, and to provide insights on biomarkers for early detection of resistance and differentiation of IGF-1R targeted therapies. Methods: The human Rhabdomyosarcoma cell line Rh41, which is sensitive to IGF-1R inhibition and responsive to both agents, was used to develop two acquired-resistant cell lines, Rh41-807R and Rh41-mAb391R. In addition, tumor xenograft models were developed from the resistant cell lines. Gene expression profiling was performed on the sensitive parental (Rh41), Rh41-807R, and Rh41-mAb391R cells and tumors to identify biomarkers involved in acquired resistance to BMS-754807 and/or mAb391. RNA expression profiles for selected biomarkers from both cells and tumors correlated well with protein expression patterns, as determined by Western blot analysis. Results: Differences in resistance mechanisms between Rh41-807 and Rh41-mAb391 resistant lines were observed and each utilizes different alternative growth signaling pathways as an escape mechanism. PDGFR was found to be overexpressed at the RNA level in both Rh41-807R cells (89-fold) and tumors (27-fold) and was constitutively activated; siRNA knockdown of PDGFR in Rh41-807R re-sensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with agents that also inhibited PDGFR in the Rh41-807R models. AXL RNA expression was found to be elevated in Rh41-mAb391R (8-fold), but down-regulated in Rh41-807R cells (5-fold). In addition, BMS-754807 was active in Rh41- mAb391R cells and able to overcome resistance to the IGF-1R antibody treated cells. However, the converse was not true i.e., mAb391 did not overcome resistance in the Rh41-807R cell line. Conclusions: PDGFR overexpression and activation may drive resistance to BMS-754807, whereas differential resistance mechanisms are involved in resistance to the IGF-1R antibody. The activity of BMS-754807 in the Rh41- mAb391R acquired-resistant model suggests that treatment with BMS- 754807 may overcome resistance in patients who have failed treatment with IGF-1R antibodies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A151.