Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma

// Matthew B. Siegel 1 , Selina Qiuying Liu 1 , Monika A. Davare 1,2 , Stephen E. Spurgeon 1 , Marc M. Loriaux 1 , Brian J. Druker 1,3 , Emma C. Scott 1,* and Jeffrey W. Tyner 1,* 1 Knight Cancer Institute, Portland, Oregon, USA 2 Department of Pediatrics at Oregon Health and Science University, Portland, Oregon, USA 3 Howard Hughes Medical Institute, Portland, Oregon, USA * These authors are co-senior authors Correspondence to: Matthew B. Siegel, email: // Keywords : BET, bromodomain, bortezomib, resistance, myeloma Received : April 10, 2015 Accepted : May 12, 2015 Published : May 20, 2015 Abstract Purpose: Despite significant therapeutic progress in multiple myeloma, drug resistance is uniformly inevitable and new treatments are needed. Our aim was to identify novel, efficacious small-molecule combinations for use in drug resistant multiple myeloma. Experimental Design: A panel of 116 small molecule inhibitors was used to screen resistant myeloma cell lines for potential therapeutic targets. Agents found to have enhanced activity in the bortezomib or melphalan resistant myeloma cell lines were investigated further in combination. Synergistic combinations of interest were evaluated in primary patient cells. Results: The overall single-agent drug sensitivity profiles were dramatically different between melphalan and bortezomib resistant cells, however, the bromodomain inhibitor, CPI203, was observed to have enhanced activity in both the bortezomib and melphalan resistant lines compared to their wild-type counterparts. The combination of bortezomib and CPI203 was found to be synergistic in both the bortezomib and melphalan resistant cell lines as well as in a primary multiple myeloma sample from a patient refractory to recent proteasome inhibitor treatment. The CPI203-bortezomib combination led to enhanced apoptosis and anti-proliferative effects. Finally, in contrast to prior reports of synergy between bortezomib and other epigenetic modifying agents, which implicated MYC downregulation or NOXA induction, our analyses suggest that CPI203-bortezomib synergy is independent of these events. Conclusion: Our preclinical data supports a role for the clinical investigation of the bromodomain inhibitor CPI203 combined with bortezomib or alkylating agents in resistant multiple myeloma.