DNAPKCs as a therapeutic target in small cell lung cancer

Small cell lung cancer is the most aggressive form of lung cancer. Current frontline treatment of anti-PD-L1 with chemotherapy only results in a modest increase in overall survival and progression-free survival due to the poor immunogenic nature of SCLC. In this investigation, we report DNAPKcs inhibition sensitizes SCLC by inducing apoptosis and DNA damage leading to micro-nuclei formation. These aberrant cytosolic DNA activates cGAS-STING pathway resulting in induction of type-I/II interferon and MHC class-I. This study provides evidence of proteasomal degradation of cMYC in a GSK3B dependent manner in response to DNAPKcs inhibition further enhancing pro-inflammatory immune pathways. Using two unique immune-competent SCLC GEM models, we show STING mediated modulation of tumor immune microenvironment by increasing CD8+ T cells, MHC-I+ cells, and M1 macrophages in response to DNAPKcs inhibition with anti-PD-L1 therapy. We further provide strong evidence of significant tumor regression in immune-competent GEMMs by treatment with DNAPKcs inhibitor alone and in combination DNAPKcsi and anti-PD-L1. Taken together this study reports induction of DNAPKcs inhibitor increases the efficacy of immune checkpoint blockade therapy remarkably by activating immune microenvironment in a STING-MYC dependent manner which is of significant translational value.