DNA Damage Response Inhibitors as Potentiators of Radiation and Immunogenicity in Merkel Cell Carcinoma

Given inherent immunogenicity, cell cycle checkpoint deficiencies and radiosensitivity, MCC is an ideal tumor to test the potential of DDRi to overcome ICI-resistance. Our preliminary data suggest that ATRi and ATMi may effectively potentiate immunogenic cell death in a VN-MCC cell line when paired with 2-4 Gy radiation, yet abrogate IFNβ production with higher radiation doses in vitro suggesting higher doses coupled with DDRi induce non-immunogenic cell death. DNA-PKi was the most potent radiosensitizer in 3 MCC cell lines by cell viability assays but less effective at inducing IFNβ. In vitro studies are ongoing to support future animal studies as we explore a potential trial for DDRi in ICI-resistant MCC.