Anti-Myeloma Activity of the Dual Akt/p70S6K Inhibitor EXEL-6075.

Abstract

Context: Akt plays a pivotal role in the survival and proliferation of multiple myeloma (MM) cells and functions as a central link between upstream signaling pathways, such as growth factor receptors (e.g. IL-6/IL-6R, IGF/IGF-1R) and the kinase PI-3K with their downstream signaling effectors, such as the multifunctional mTOR-p70S6K cascade. The pivotal role of Akt in these proliferative/anti-apoptotic cascades for MM has provided the impetus for development of small molecule inhibitors against the kinase activity of Akt. We show that the dual Akt/p70S6K kinase inhibitor EXEL-6075 has potent anti-MM activity in preclinical models.Methods/Results: We tested a panel of 15 human MM cell lines for in vitro response to EXEL-6075 using MTT colorimetric survival assays, which showed that the majority of MM cells responded to EXEL-6075 with IC50 values <0.5 μM, including a subset of 6/15 MM cell lines with IC50 values in the range of 0.1 μM. Importantly, <16 hrs of exposure to 0.5 μM of EXEL-6075 was sufficient to commit these EXEL-6075-sensitive MM cell lines to cell death. Peripheral blood mononuclear cells (PBMCs) remain insensitive to the drug up to 5 μM, consistent with a 1-log therapeutic window compared to the aforementioned sensitive MM cell lines. Other non-malignant tissue, such as bone marrow stromal cells (BMSCs) and immortalized human hepatocyte cells were even less sensitive to EXEL-6075 (IC50>5 μM), further underscoring its selectivity towards neoplastic cells. EXEL-6075-responsive cells included MM cells resistant to diverse conventional and novel agents, such as dexamethasone, bortezomib, and immunomodulatory thalidomide derivatives, suggesting that dual Akt/p70S6K inhibition may overcome mechanisms of constitutive resistance to other currently available therapeutics. EXEL-6075 was also able to overcome the protective effects of IGF-1 and IL-6 on MM.1S cells. In addition, there was modest, if any, protection conferred to MM cells by BMSCs at low drug doses. Interestingly, when we compared the in vitro activity of EXEL-6075 against cell lines from MM vs. other neoplasias (including 11 epithelial cancer cell lines which also exhibited dose-dependent response to this kinase inhibitor), EXEL-6075 was significantly more active against MM cells, as evidenced by the distribution of IC50 values and AUCs of the dose-response curves for each group of cell lines (p=0.028, t-test). Ongoing studies are utilizing gene expression profiles of MM cells highly- vs. moderately-responsive to EXEL-6075, in order to identify putative markers of sensitivity vs. resistance to this kinase inhibitorConclusion: Targeting the Akt-mTOR-p70S6K pathway is an attractive strategy for the treatment of MM due to the central role Akt plays in proliferation and survival of MM. Inhibition of Akt using the small molecule inhibitor EXEL-6075 resulted in sub-μM killing of MM cell lines with > 1-log differential activity against the non-neoplastic tissues tested in our study. This remains an interesting strategy for the treatment of MM. Future in vivo studies will be needed to confirm these interesting in vitro results.