Intersectional Screening Identifies Synergistic Combinatorial Therapies for Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Merkel cell polyomavirus is integrated into the host genome in the majority of MCC tumors (virus‐positive MCC; VP‐MCC). The remainder of MCC tumors are virus‐negative (VN‐MCC) and are associated with mutations induced by ultraviolet light. Immune checkpoint inhibitors (ICI) can produce durable responses in some cases of MCC, but many patients cannot receive ICI or have disease progression despite immunotherapy. In order to find alternative treatments, we performed high‐throughput small molecule and functional genomics screens. We screened ~4,000 compounds for their ability to reduce the viability of VP‐MCC and VN‐MCC cells relative to control cell lines. We identified navitoclax, a Bcl‐2 family inhibitor, as selectively efficacious against VP‐MCC compared to VN‐MCC and control cell lines. Interestingly, our functional genomics screen independently identified Bcl‐xL, one target of navitoclax, as being essential for VP‐MCC viability, further supporting Bcl‐xL inhibition as a potential treatment for VP‐MCC. However, clinical use of navitoclax is limited by a dose‐dependent thrombocytopenia. To address this problem, we performed a synergy screen combining navitoclax with each of ~2000 compounds to identify drug combinations with a higher efficacy and a lower risk of thrombocytopenia. This combination study revealed synergistic effects between navitoclax and multiple drug categories including FDA‐approved DNA‐damaging drugs. Preliminary data showed synergy in preclinical xenograft mouse models of MCC. Overall, our intersectional screening approach identified new combinatorial therapies that are potentially more efficacious with lower side effect profiles, and since these treatment combinations rely of FDA‐approved drugs, they will be instantly accessible to patients who do not benefit from ICI therapy.