High‐Throughput Matrix Synergy Screening Identifies Novel Therapeutic Combinations for Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The majority of MCC tumors are virus‐positive (VP‐MCC) with Merkel cell polyomavirus integrated into the host genome, whereas virus‐negative (VN‐MCC) tumors are associated with mutations induced by ultraviolet light exposure. Primary MCC is treated by surgical resection and radiotherapy. For metastatic MCC, conventional chemotherapy is ineffective, and although immune checkpoint inhibitors (ICI) can produce durable responses in some cases, many MCC patients cannot receive ICI and others have disease progression despite immunotherapy. To identify novel treatments for MCC, we performed high‐throughput small molecule screening of ~4,000 FDA‐approved and experimental drugs for their ability to reduce MCC viability in VP‐MCC and VN‐MCC cell lines relative to immortalized control cell lines. Drugs were grouped by target and ranked according to area under dose‐response curve (AUC). We identified navitoclax as selectively efficacious against VP‐MCC cell lines compared to VN‐MCC and controls. However, navitoclax use in the clinic is limited by a dose‐dependent thrombocytopenia. To identify drug combinations that will lower the effective dose of navitoclax and thereby decrease the risk of thrombocytopenia, we performed a synergy screen combining navitoclax with each of the 1912 clinically relevant compounds in the NCATS Mechanism Interrogation PlatE (MIPE) library. This combination study revealed synergistic effects between navitoclax and multiple drug categories. We are now testing high priority drug combinations for toxicity and efficacy in pre‐clinical xenograft models of MCC. Collectively, our study has identified novel therapeutic drug combinations for MCC with the potential for enhanced efficacy and lower side effect profiles. By focusing on repurposing approved drugs, these combinations will be immediately available to patients who fail ICI therapy.Support or Funding InformationNIH Intramural Research Program