Lung cancer is a devastating disease that remains the top cause of cancer mortality and accounts for a quarter of all cancer related deaths. The recent introduction of immunotherapy has led to a paradigm shift in the treatment of lung cancer patients. Unfortunately, only a subset of patients respond to currently approved immunotherapies and many patients develop resistance soon after initial response. Hence, new immunotherapies and drugs that synergize with immunotherapy are urgently needed to further help patients. This proposal is based on intriguing recent clinical reports which showed that patients with mutations in a gene called SMARCA4 do not respond to immunotherapy and have very poo...

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Lung cancer is a devastating disease that remains the top cause of cancer mortality and accounts for a quarter of all cancer related deaths. The recent introduction of immunotherapy has led to a paradigm shift in the treatment of lung cancer patients. Unfortunately, only a subset of patients respond to currently approved immunotherapies and many patients develop resistance soon after initial response. Hence, new immunotherapies and drugs that synergize with immunotherapy are urgently needed to further help patients. This proposal is based on intriguing recent clinical reports which showed that patients with mutations in a gene called SMARCA4 do not respond to immunotherapy and have very poor outcomes. Interestingly, our recent work in various models of lung cancer and studies in human lung cancer cells with mutations in SMARCA4 indicate that SMARCA4 mutant tumors have very low levels of key immune cells known as dendritic cells that are required for anti-tumor immunity. Thus, we plan to investigate how lack of dendritic cells within SMARCA4 mutant tumors affects immunotherapy. Importantly, we aim to test a dendritic cell rejuvenation therapy to try to jump start the immune system. Further, we developed drug-like molecules that induce the destruction of SMARCA2, a protein required for survival of SMARCA4 mutant cancer cells, termed SMARCA2 PROTACs (PROteolysis TArgeting Chimeras). Hence, we aim to study whether SMARCA2 PROTACs can help potentiate the activity of FDA approved immunotherapies. In conclusion, the overarching goal of this project is to determine the molecular mechanisms leading to resistance of SMARCA4 mutant tumors to immunotherapy and to overcome this resistance by leveraging dendritic cell-directed therapy and novel SMARCA2 PROTACs. If successful, our study will provide new insights into mechanisms as well as approaches to overcome immunotherapy resistance.

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