Pdcd4-Rictor Interaction in Suppression of Lung Tumorigenesis

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Project Summary/Abstract Lung cancer is the leading cause of cancer-related deaths in the United States. The high mortality rate is not only due to the lack of effective early detection but also due to poor tumor response to currently available therapies. These underscore the urgent need to better understand the biological events and mechanism of lung cancer suppression, as is the need for important new therapeutic approaches that specifically target these processes to improve survival rates. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter of which accounts for 80-85% of all cases. A new subset of lung cancer in both SCLC and NSCLC was recently identified in which Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified. Rictor is an essential component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for mTORC2 complex activity and integrity. Activation of mTORC2 results in promotion of cancer cell proliferation and survival. This application builds on exciting preliminary data that Programmed cell death 4 (Pdcd4) bound with Rictor through a Rictor binding domain (RBD) to inhibit mTORC2 activity, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) level, cell proliferation, and colony formation. In addition, a peptide containing the RBD specifically inhibits mTORC2 but not mTORC1. Our data further demonstrated that the RBD peptide suppressed NSCLC proliferation in cultured cells and nude mice. The central hypothesis is that Pdcd4-Rictor binding specifically inhibits mTORC2 to preferentially suppress proliferation in Rictor-elevated NSCLC via induction of proteasomal degradation of PFKFB3. To test this hypothesis, three specific aims are proposed: i) Delineate the mechanism of how Pdcd4-Rictor binding interferes with mTORC2 activity to suppress tumor growth in NSCLC; ii) Dissect how Pdcd4-Rictor-mTORC2 axis impacts PFKFB3 stability and metabolic pathways; iii) Demonstrate that mTORC2-specific inhibition by RBD peptide preferentially suppresses the growth of Rictor-elevated NSCLC to improve survival rate. The accomplishment of the proposed study will not only uncover novel regulatory mechanisms of mTORC2 activity and PFKFB3 expression by Pdcd4 but also reveal the importance of mTORC2-specific inhibition by RBD peptide on NSCLC tumorigenesis. The expected findings will guide us to develop new strategies that are particularly relevant to precision medicine approaches for NSCLC patients with elevated Rictor.