The Role of Actin Capping Proteins in Homology Directed DNA Repair and Therapeutic Response to Radiation and Immunotherapy
Immune checkpoint inhibitors (ICIs), which activate a patient’s immune system to fight cancer, have shown remarkable efficacy. However, many patients relapse. ICIs combined with radiation therapy can increase a patient’s response to treatment. We conducted a genome-scale CRISPR screen in mouse melanoma cells and identified that actin capping proteins are involved in cell survival after radiation or ICI treatment. Inactivation of these proteins led to impaired homology-directed DNA repair. This activates the STING signaling pathway and the expression of proteins on cancer cells that protect them from the immune system. We will determine if treatment of cancer cells with small molecule inhibitors targeting these actin capping proteins increases DNA damage after radiation treatment. We will also identify the regions of DNA that are most vulnerable to DNA damage. We will then perform in vivo studies in mice to validate our in vitro work and demonstrate its translational potential.
