491 Functional genomics screen identifies alternative targetable pathways for Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Most MCC tumors have Merkel cell polyomavirus integrated into the host genome (virus-positive MCC; VP-MCC), whereas virus-negative MCC (VN-MCC) tumors bear UV-induced mutations. Immune checkpoint inhibitors (ICI) are the first-line treatment for metastatic MCC, but the majority of patients are either not candidates for ICI or have disease progression while on treatment. In order to identify alternative therapeutic targets for these patients, we performed a druggable genome RNAi screen in MKL-2 (VP-MCC) and MCC26 (VN-MCC) cell lines. We screened >25,000 siRNA for their ability to reduce MCC viability at 72 hours. The main gene functions identified as essential to MCC viability included cell proliferation (VP- and VN-MCC) and apoptosis (VP-MCC). These results were corroborated by a follow-up RNAi screen including the two original cell lines, WaGa (VP-MCC), MCC13 (VN-MCC), and UISO (VN-MCC). Interestingly, many essential gene products identified in our screen were targets of compounds that selectively reduced MCC viability in an independent high-throughput MCC viability screen of ∼4000 small molecules. High-priority lead compounds supported by both screens showed efficacy in preclinical xenograft mouse models of MCC. Overall, our discovery and validation of novel targetable pathways have identified alternative treatment approaches for metastatic MCC.