A Novel Peptide to Inhibit Rictor-amplified Lung Tumorigenesis

Lung cancer is the first leading cause of cancer-related deaths in United States, and Kentucky leads the nation in lung cancer incidence and mortality. The high mortality rate is not only due to the lack of effective early detection, but also because of poor tumor response to currently available therapies. This underscores the urgent need to decipher novel strategies for cancer intervention and to identify new agents for cancer therapeutics. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), in which NSCLC accounts for 80-85% of all cases. A new subset of lung cancer patients in both SCLC and NSCLC was recently identified that Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified. Rictor is an essential component of mTORC2 and required for mTORC2 complex activity and integrity. Treatment of Rictor up-regulated lung cancer cells showed that these cells are more sensitive to dual mTORC1 and mTORC2 inhibitors than mTORC1 specific inhibitors. These findings point to the specific inhibition of mTORC2 activity as a potentially promising therapeutic strategy for Rictor up-regulated lung cancer patients. However, a test of this concept requires identification of an mTORC2-specific inhibitor. By study the function of a tumor suppressor, Programed cell death 4 (Pdcd4), in suppression of tumorigenesis, Pdcd4 was found to bind with Rictor through the Rictor binding domain (RBD). Exciting preliminary findings showed that the synthesized peptide that carries the sequence of RBD suppressed mTORC2 but not mTORC1 activity as well as Akt phosphorylation in lung cancer cells. This RBD peptide, thus, provide a unique tool to study the effects of inhibition of mTORC2 activity on lung tumorigenesis. The central hypothesis is that the RBD peptide effectively inhibits tumor growth in Rictor up-regulated lung cancer cells. To test this hypothesis, two specific aims are proposed: i) demonstrate that RBD binds to Rictor to inhibit tumor growth in lung cancer cells with elevated-Rictor; ii) define the upregulation status of Rictor expression and inhibitory role of RBD peptide in Kentucky lung cancer patients. Accomplishment of the proposed study will not only uncover a novel regulatory mechanism of mTORC2 activity by Pdcd4-Rictor binding but also enable us to demonstrate the importance of inhibition of mTORC2 activity by the peptide in suppression of tumor growth. This novel peptide has the potential to lead to development of new therapeutic agents that are particularly relevant for precision medicine approaches for patients with up-regulated Rictor.