Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. MCC is virus-positive (VP-MCC) in the majority of cases wherein Merkel cell polyomavirus is integrated into the host genome. The remainder of cases are virus-negative (VN-MCC) and are associated with mutations induced by ultraviolet light. Primary MCC is effectively treated by surgical resection and radiotherapy, but for metastatic MCC, outcomes for conventional chemotherapy are poor. Immune checkpoint inhibitors are more likely to produce durable responses in metastatic MCC, but they are not effective in all cases and are not a viable option for patients with immunosuppression. To address the need for better therapeutic options, we utilized high-throughput small molecule screening to assess the efficacy of ~4,000 drugs in reducing VP-MCC and VN-MCC viability. Among the compounds we screened, navitoclax was identified as an effective agent against VP-MCC cell lines, compared to VN-MCC or control cells. However, navitoclax clinical application is limited by dose-dependent thrombocytopenia. One strategy to reduce thrombocytopenia risk is to combine a lower dose of navitoclax with another MCC-effective agent. To identify effective drug combinations, we performed a synergy screen with 1912 pairings of navitoclax with each of the clinically relevant compounds in the NCATS Mechanism Interrogation PlatE (MIPE). We were able to identify synergy between navitoclax and multiple drug classes. High priority drug combinations are now being evaluated for toxicity and efficacy in pre-clinical xenograft models of MCC. Our study has identified novel therapeutic combinations for the treatment of VP-MCC. By focusing on drugs already in clinical use, validated combinations will be quickly available to patients for whom immunotherapy is not available or effective.
Citation Format: Khalid Garman, Tara Gelb, Daniel Urban, Matthew Hall, Isaac Brownell. High throughput synergy screening identifies therapeutic combinations for Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4034.