Project 1

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PROJECT 1 SUMMARY IDENTIFYING METABOLIC VULNERABILITIES REGULATED BY THE P53 FAMILY IN LUNG CANCER p53 is commonly mutated in all subtypes of human lung cancer. p53 is part of a family of genes that includes p63 and p73. The functions of p63 and p73 are beginning to be understood in contexts in which p53 function has been well established including tumor suppression and metabolism. The complexity of p63 and p73 function is due in part to the existence of multiple isoforms that previously could not be studied independently in vivo. Full length TA isoforms of p63 and p73 contain a transactivation domain, structurally and functionally resembling p53, whereas the ΔN isoforms of p63 and p73, while also possessing transactivation activity, antagonize the activities of p53 and the TA isoforms of p63 and p73. Interestingly, mutant p53, present in a wide variety of human cancers, has been shown to interact with TAp63 and TAp73 to inactivate their tumor-suppressive function. This interaction has also been shown to be partly responsible for gain of function activity of p53 mutants. Moreover, ∆Np63 and ∆Np73, which are amplified in many cancers, including non-small cell lung cancer, bind and inhibit the activity of p53, TAp63, and TAp73. Lung cancer subtypes also share ∆Np63 driven transcriptional signatures (Abbas et al., Cancer Research, 2017). We have shown previously that p53 deficient and mutant tumors can be metabolically reprogrammed to decrease tumor glycolysis and result in tumor regression through downregulation of ∆Np63 or ∆Np73 (Venkatanarayan et al., Nature, 2015; Napoli et al., Cancer Cell, 2016). Although our knowledge on the functions of the p53 family in cancer has expanded, their roles in tumor metabolism are not understood, and the metabolic pathways regulated by the p53 family members in lung cancer have not been examined. Our overarching goal is to understand the metabolic pathways regulated by the p53 family in lung cancer to develop strategies to target p53 mutant cancers. We have made great strides toward this goal by generating p63/p73 isoform-specific conditional knockout mice to allow for temporal and context dependent deletions of each isoform. These tools have allowed us to gain a greater mechanistic understanding of the interplay of the p53 family in cancer. We have recently demonstrated that conditional deletion of ∆Np63 in the KrasG12D mouse model of lung adenocarcinoma results in dramatically decreased lung tumor burden. Additionally, we have found that KrasG12D/+;TAp73∆td/∆td mice develop increased and more aggressive lung adenocarcinomas that phenocopy mouse models with Kras and p53 mutations, similar to the ones found in human lung cancer. Lastly, we have developed a novel mouse model of small cell lung cancer (SCLC) lacking TAp73, which is mutated in 10% of cases. The phenotypes of these mice are associated with changes in key metabolic pathways including glycolysis and cysteine metabolism. Our primary objective in this application is to define and understand metabolic pathways regulated by the p53 family in lung cancer. Based on our published work and preliminary data, we hypothesize that ∆Np63 can be downregulated to metabolically reprogram tumor cells and the microenvironment to compensate for p53 dysfunction.