Abstract 5830: Combination of volasertib (BI6727) and abemaciclib (LY2835219) for melanoma management: Concomitant targeting of multiple cell cycle phases

Melanoma is one of the most lethal forms of skin cancer that kills an average of around one person every hour in the United States alone. Melanoma can be surgically removed if diagnosed early, however, undiagnosed or untreated melanomas can rapidly metastasize to become lethal. Significant progress has been made in the treatment of metastatic melanoma over the past decade, especially with novel targeted therapeutic approaches (such as BRAF- and MEK- inhibitors or immunotherapies). However, even with these newer therapies, melanoma can acquire resistance and become untreatable, with fatal consequences. Therefore, novel therapeutic approaches are required for the management of this neoplasm. It is commonly accepted that mechanism-based combination therapeutics could be better for an efficient and complete elimination of cancer cells, thereby limiting the chances of recurrence and resistance. Based on this rationale, we reasoned that a simultaneous targeting of G2/M and G1 phases of the cell cycle could provide a more efficacious response against melanoma. Studies in our laboratory have suggested that polo-like kinase 1 (PLK1), which is a mitotic regulator acting in the G2/M phase of the cell cycle, is overexpressed in melanoma and is a potentially druggable target for melanoma management. We demonstrated that BI6727, a small-molecule PLK1 inhibitor, resulted in delay and regression of melanoma xenografts. Similarly, dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway has been shown to frequently occur in melanoma, and CDK4/6 inhibition is being extensively investigated in the management of several cancers, including melanoma. In this study, we evaluated the anti-proliferative efficacy of a combination of G2/M-phase targeting by BI6727 and G1-phase targeting by the CDK4/6 inhibitor LY2835219 in human melanoma cells. We determined the effect of BI6727 and/or LY2835219 on growth and viability of human melanoma cells using the RealTime-Glo Cell Viability- and Trypan Blue exclusion- assays. We found that the combination of BI6727 and LY2835219 resulted in a better anti-proliferative response, when compared to either of the agents alone. Further, the combination treatment was found to result in a marked decrease in the clonogenic survival of melanoma cells, as assessed by colony formation assay. Cell cycle analysis showed a G2/M-phase arrest in BI6727 treated cells and G1-phase arrest in LY2835219 treated cells. Interestingly, the combination was found to cause G2/M as well as G1- phase arrest of melanoma cells. Overall, our data suggests that a concomitant inhibition of PLK1 with CDK4/6 provides a superior anti-proliferative response, suggesting that dual inhibition should be further evaluated in detailed in vitro and in vivo experiments. Additional studies to determine the mechanisms of this combination are currently underway in our laboratory. Citation Format: Sanghamitra Nethramurthy, Mary A. Ndiaye, Chandra K. Singh, Nihal Ahmad. Combination of volasertib (BI6727) and abemaciclib (LY2835219) for melanoma management: Concomitant targeting of multiple cell cycle phases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5830.