674 The effective killing of the difficult-to-treat melanomas with the combinations of MCL1 inhibitors S63845/MIK665 plus Navitoclax

Abstract

Despite the advancement of melanoma care, a subset of melanoma patients do not respond or relapse with current targeted or immuno-therapies. Therefore, it is necessary to explore other biological processes can be therapeutic. The BCL-2 family of proteins contributes to a cancer cell’s resistance to treatment, and BH3 mimetics drugs that target BCL-2 are effective in hematological cancers. We used genetic knockdown and BH3 mimetics therapeutics to target BCL-2’s anti-apoptotic defenses, and identified MCL1 and BCLXL as crucial melanoma pro-survival members. We then examined the effects of combining BH3 mimetics that target MCL1 and BCLXL in vivo and in vitro. We prioritized clinical-trial-ready compounds, such as ABT263 (Navitoclax) and S63845/S64315 (MIK655). We used commercial cell lines, as well as cells derived from patients with difficult-to-treat melanomas. The melanoma panel included the subtypes acral, mucosal, superficial spreading, and nodular, as well as diverse mutations, such as wild type for BRAF, NRAS and NF1. In vitro, the combined inhibition of MCL1 and BCLXL resulted in greater killing than either single agent (p < 0.05) in multiple assays. Genetic knock-down and knock-out studies showed that the combination-induced cell death was not dependent on pro-apoptotic BCL2 family members BID, BIM, or NOXA. Moreover, in mouse xenograft model, the combination inhibited tumor growth of multiple melanomas (p <0.01), had tolerable toxicity, and reduced sphere forming capacity (p < 0.05) in a downstream in vitro assay. In summary, this study suggests that dual targeting of MCL1 and BCLXL can be an alternative treatment for melanoma patients who have exhausted current treatment options.