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

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.

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.

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-naïve 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-naïve 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-naïve 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.

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.

No relevant conflicts of interest to declare.