Despite significant progress in the past decade non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality world-wide. Particularly challenging among NSCLC patients are those whose tumors harbor mutations in KRAS (~30% of lung adenocarcinomas), that account for ~25,000 deaths annually in the US. Since 2015, immunotherapy (IO) with PD-1/PD-L1 inhibitors has transformed NSCLC clinical practice; however only ~ 25% of KRAS-mutant NSCLC respond to PD-1/PD-L1 inhibitors. Improved understanding of the immunobiology of KRAS-mutant NSCLC and development of novel immunotherapeutic strategies are critical in order to improve clinical outcomes. We previously identified that...

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Despite significant progress in the past decade non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality world-wide. Particularly challenging among NSCLC patients are those whose tumors harbor mutations in KRAS (~30% of lung adenocarcinomas), that account for ~25,000 deaths annually in the US. Since 2015, immunotherapy (IO) with PD-1/PD-L1 inhibitors has transformed NSCLC clinical practice; however only ~ 25% of KRAS-mutant NSCLC respond to PD-1/PD-L1 inhibitors. Improved understanding of the immunobiology of KRAS-mutant NSCLC and development of novel immunotherapeutic strategies are critical in order to improve clinical outcomes. We previously identified that mutations in genes that co-occur with KRAS (“co-mutations”) impact the response of KRAS-mutant NSCLC to PD-1/PD-L1 inhibition. This proposal will dissect the immune-modulating and immunotherapy-modifying effects of mutations in RBM10, one of the most frequently co-mutated genes in KRAS-mutant NSCLC (~25%). We have developed preliminary data indicating that loss of RBM10 promotes activation of cellular immune pathways. In aims 1 of this proposal, we will dissect mechanisms by which loss of RBM10 triggers activation of cellular immune and inflammatory pathways in KRAS-mutant NSCLC. In aim 2, we will seek to identify novel tumor antigens arising as a result of RBM10 loss that can be recognized and targeted by the immune system. In aim 3, we will comprehensively evaluate how loss of RBM10 affects clinical responses to immunotherapy with immune checkpoint inhibitors and we will evaluate novel combination therapeutic strategies aimed at enhancing the effects of PD-1/PD-L1 inhibition in RBM10-mutant non-small cell lung cancer. Thus, this proposal addresses a major unmet clinical need and has the potential to open new avenues for immune targeting of KRAS-mutant non-small cell lung cancer that can be rapidly translated to the clinic.

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