Drug resistance is a major cause of concern in cancer chemotherapy that not only reduces efficacy but also causes toxicity through overdosing. For example, Ixazomib, an oral proteasome inhibitor, has proven to remarkably improve myeloma patient outcomes but is associated with dose limiting toxicities and drug resistance. Therefore, new combination treatment regimens are urgently needed for the treatment of cancers, including multiple myeloma, which can lower the required dose of standard-of-care drug without compromising on treatment efficacy. We will present an optimization-regularization based computational prediction method called secDrug that uses large-scale pharmacogenomics databases to identify novel secondary drug combinations to reverse drug resistance. In this study, we applied secDrug to Ixazomib-resistant cell lines (>100) in the Genomics of Drug Sensitivity in Cancer (GDSC) database and predicted that the following FDA-approved drug classes can be best combined with Ixazomib to overcome resistance in MM: nicotinamide phospho ribosyl transferase or Nampt inhibitor (FK866), HDAC inhibitors (Panobinostat, SAHA), neddylation inhibitor (MLN4924), Raf inhibitor (PLX-4720) and HSP90 inhibitor (17-AAG). Our results corroborate with earlier studies that have indicated these drugs could potentially be used in MM, alone or in combination. To validate our prediction results, we treated our panel of >50 human multiple myeloma cell lines (Ix-sensitive and Ix-resistant HMCLs) with the top predicted drug combination - FK866 + Ixazomib. The results, based on combination index theorem, show that this combination works highly synergistically where the IC50 of ixazomib in MM cells was significantly reduced in presence of FK866. Similar results were obtained for the other top predicted combination regimens. Our findings provide a strong case for using secDrug for predicting secondary drugs in cancers resistant to the standard-of-care therapy. Furthermore, this provides additional evidence in support of combining FK866 with ixazomib to enhance sensitivity or overcome resistance to ixazomib and thereby improve patient outcome. Our future aim is to investigate the mechanism behind the synergism between proteasome inhibitors and the top drugs identified by our algorithm as candidates for secondary combination therapies using next-gen transcriptomics and single-cell approaches.

Citation Format: Harish Kumar, Ujjal Kumar Mukherjee, Sayak Chakravarti, Li Chen, Brian Van ness, Amit Kumar Mitra. A novel computational combination-therapy prediction algorithm (secDrug) identifies the Nampt inhibitor FK866 reverses PI-resistant multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-266.

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.