Dexamethasone synergizes with MCL-1 inhibition in multiple myeloma through suppression of S6 phosphorylation

Abstract

The number of anti-cancer drugs that are approved for clinical use or in late-stage clinical trials for treatment of multiple myeloma is extensive and rapidly increasing. However, drug resistance and relapse after treatment are still very common problems. There is an unmet need for a strategy to identify logical combinations of (partially) successful drugs to reach synergistic effects. Testing all possible drug combinations and redefining pharmacodynamics for combination treatments is practically challenging. Therefore, we performed a lethality screen in three human multiple myeloma cell lines (HMCLs) in which we combined two drugs representing different drugs classes, including classical chemotherapeutics, proteasome inhibitors, pro-survival BCL-2 protein family inhibitors, HDAC inhibitors and corticosteroids to test for synergy. Of the twenty-eight combinations tested, seven showed synergistic effects in all three HMCLs. The combination of dexamethasone with the specific MCL-1 inhibitor S63845 was found to be the most potent, resulting in strong synergistic killing with average combination indexes of 0.3-0.5. In accordance with literature we observed a minor increase in dexamethasone-induced BIM mRNA and protein expression. Additional kinome analysis of HMCLs revealed a reduction in Akt kinase activity upon dexamethasone treatment. We did not observe downstream effects on nuclear FOXO1/3a levels or localization but did detect a great reduction in phosphorylation of ribosomal protein S6 on both serine 235/236 and 240/244 positions. Inhibition of S6 phosphorylation by a S6K1 inhibitor also had synergistic effects on cell death in combination with MCL-1 inhibition. This suggests that a S6K1 inhibitor might be used as a substitute of dexamethasone in the combinatorial treatment with MCL-1 inhibitors. In conclusion, we reveal a novel molecular mechanism mediated by Akt and S6 phosphorylation that is underlying synergy between dexamethasone and MCL-1 inhibition in multiple myeloma.