High‐Throughput Screening Identifies Novel Therapeutic Targets for Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The majority of tumors are virus‐positive MCC (VP‐MCC) as they have Merkel cell polyomavirus integrated into the host genome. The remainder of tumors are virus‐negative (VN‐MCC) and are associated with ultraviolet light mutations. Primary MCC is treated by surgical resection and radiotherapy. Conventional chemotherapy is ineffective for metastatic MCC, but immune checkpoint inhibitors (ICI) can produce durable responses. However, some 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 drugs for their ability to reduce MCC viability in VP‐MCC and VN‐MCC cell lines. Out of the compounds screened, 39 reduced viability in MCC cell lines relative to immortalized control cell lines. The 39 identified compounds were categorized into compounds reducing viability in all MCC cell lines (n=14); only in VP‐MCC cell lines (n=23); or only in VN‐MCC cell lines (n=2). The targets of high priority compounds were validated using RNA interference (RNAi) and in vivo efficacy was confirmed in preclinical xenograft mouse models. Collectively, our studies identify new potential pharmacological targets for treating VP‐MCC and VN‐MCC.Support or Funding InformationNIH Intramural Research ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.