Blockade of IGF-1R with OSI-906 Overcomes Bortezomib-Resistance in Multiple Myeloma

Abstract Abstract 925 Blockade of IGF-1R with OSI-906 Overcomes Bortezomib-resistance in Multiple Myeloma Deborah J. Kuhn, Hua Wang, Richard J. Jones, Chad C. Bjorklund, Robert Z. Orlowski The Department of Lymphoma & Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX Intro: Bortezomib (Velcade®) therapy is now one of the standards of care in the treatment of newly diagnosed and relapsed/refractory multiple myeloma. Unfortunately, like many other novel agents, the emergence of drug resistance often results in a reduced response to any subsequent therapies that contain bortezomib. Identifying the molecular signaling pathways predominant in bortezomib-resistance can lead to the discovery of therapies that can overcome or prevent the emergence of such resistance all together. Design: In order to improve our understanding of the mechanisms responsible for bortezomib-resistance, our group has developed cell line models of interleukin (IL)-6-dependent and –independent bortezomib-resistant multiple myeloma. Results: Gene expression profiling identified insulin-like growth factor (IGF-1) signaling as one pathway that was induced in bortezomib-resistant myeloma cell lines. Its role was validated in molecular studies that showed exogenous IGF-1 protected drug-naive cells from bortezomib, while shRNA-mediated knockdown of the IGF-1 receptor (IGF-1R) in bortezomib-resistant models restored sensitivity to this proteasome inhibitor. We then evaluated whether targeting IGF-1R with the clinically relevant inhibitor OSI-906 (OSI Pharmaceuticals, Inc.) could be a valid strategy to overcome bortezomib-resistance. OSI-906 alone preferentially induced cell death in bortezomib-resistant cell lines, while drug-naive cell populations were relatively spared. Simultaneous addition of bortezomib and increasing concentrations of OSI-906 enhanced the amount of cell death. Also, OSI-906 preferentially induced apoptosis as measured by Annexin V staining. Knockout of IGF-1R gene expression using lentiviral shRNAs in bortezomib-resistant cell lines decreased sensitivity to OSI-906 compared to their scrambled control counterparts, underscoring the importance of IGF-1R signaling in these cells. Conversely, lentiviral overexpression of IGF-1R in drug-naive wild-type cell lines reduced apoptosis when these models were exposed to OSI-906. Next, we determined whether OSI-906 alone would have an effect on MDA-MM-002, a cell line developed from the pleural effusion of a patient with advanced myeloma. MDA-MM-002 cells, which are resistant to a number of chemotherapeutics, including bortezomib, showed no decrease in viable cell populations when treated with OSI-906 alone. However, when combined with bortezomib, there was a dose-dependent decrease in the viable cell population. Importantly, flank xenograft models of bortezomib-resistant myeloma cells in immunodeficient mice remained insensitive to bortezomib treatment, but showed a dose-dependent response to OSI-906 as evidenced by decrease tumor cell growth, and caspase-3 and PARP cleavage. Examination of synergy profiles using isobologram analysis demonstrated a high degree of synergy with OSI-906 and bortezomib over the use of either drug alone. Conclusions: In addition to the important role of IGF-1 in myeloma biology, the findings herein provide an excellent rationale for using OSI-906 to target IGF-1 signaling in combination with bortezomib as an approach to overcome, or possibly even prevent outgrowth of resistance to bortezomib in myeloma patients. Disclosures: No relevant conflicts of interest to declare.