Paradoxical Effects of SETD2 Inactivation in EGFR- and KRAS-driven Lung Adenocarcinoma

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PROJECT SUMMARY Mutual exclusivity and co-occurrence of cancer causing mutations are due to pairwise genetic relationships that include oncogenic redundancy and synthetic lethality. These interactions suggest that the cancer-promoting effects of one mutation are dependent on the presence of another, a contingency that can be exploited in the development of new cancer therapies. Certain mutations have contrasting effects, promoting cancer in one mutational context but limiting it in another. SETD2 inactivation in lung adenocarcinoma occurs in 9% of tumors overall, and frequently co-occurs with oncogenic KRAS, but is mutually exclusive with oncogenic EGFR, the most frequent driver genes of this disease. Our lab was the first to identify SETD2 as a potent tumor suppressor in a KRAS-driven mouse model. However, paradoxically, Setd2 inactivation prevents tumor growth in the context of oncogenic EGFR, suggesting an antagonism between these alterations. The opposing effects of Setd2 inactivation are surprising given that KRAS is directly downstream of EGFR and activates the MAPK pathway, a driver of many cancer types. Given that KRAS and EGFR share this major tumorigenic pathway, I hypothesize that Setd2 inactivation is specifically synergistic with activation of the MAPK pathway, but incompatible with a separate pathway that is also downstream of EGFR. An important clue in deciphering this incompatibility is the epistatic relationship between SETD2 and LKB1, another frequently inactivated gene. Although both genes are powerful tumor suppressors in KRAS- driven models, co-mutation conferred no additional growth advantage, indicating that these genes act in the same pathway. Additionally, Lkb1 inactivation has the same paradoxical antagonism in EGFR-driven tumors. Inactivation of Lkb1 results in constitutively activated mTORC1 signaling which is a common feature of many cancers. My preliminary data demonstrate that Setd2 inactivation also promotes mTORC1 activity in KRAS- driven tumors. Likewise, oncogenic EGFR directs mTORC1 signaling via the PI3K-AKT axis and is reliant on this pathway for tumor maintenance, while oncogenic KRAS is not. Given the stimulation of mTORC1 signaling by Setd2 and its synthetic lethality with oncogenic EGFR which also activates mTOR, I hypothesize that the heightened mTORC1 activity present in Setd2-inactivated tumors is incompatible with oncogenic EGFR. To test these hypotheses, I first aim to determine whether Setd2 inactivation is synergistic with oncogenic MAPK signaling using a BRAF-driven mouse model. Second, I will determine whether excess mTORC1 signaling is responsible for EGFR-SETD2 antagonism by modulating this pathway in each driver context using tumor cell lines. This study will begin to characterize the synthetic lethal relationship between two frequently mutated genes in lung adenocarcinoma. Understanding these interactions will enable development of new therapies that target genotype specific vulnerabilities.