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. RNA.seq analysis data of small cell lung cancer cells, DMS114, H146, H196, H446, H720 and H1341 comparing only DMSO treated (control) and NU7441 treated cells.