Identification and targeting of the signaling pathways underlying lung cancer.

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DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide, with 5-year survival rates of <15%, and this is largely due to the lack of effective treatments for advanced disease. Activating mutations of the K-ras gene are found in more than 30% of lung adenocarcinoma, indicating that mutant K- ras is a driver of lung cancer and an important target for therapeutic intervention. However, previous attempts to directly target mutant K-ras have met with little success. Thus, alternative approaches to target activated K-Ras signaling are warranted. Our long-term goals are to identify effectors that are required for mutant K-Ras-driven tumorigenesis and to develop therapeutic approaches to targets these molecules and pathways. Our Preliminary Studies, along with recent findings from others, suggest that Notch signaling pathways are potentially important therapeutic targets in non-small cell lung cancer (NSCLC). The Notch family consists of four receptors in mammals (Notch1-4) and current approaches to Notch inhibition involve the use of ?-secretase inhibitors (GSIs), which inhibit the activation of all four receptors. Unfortunately, the use of GSIs in patients is limited due to severe intestinal toxicities that are a result of global Notch inhibition. In additin, recent studies indicate that the different Notch receptors have distinct and non-overlapping functions in tumorigenesis and that these functions are cell type and timing-dependent. These finding suggest that anti-cancer therapies targeting Notch receptors and their downstream signaling pathways need to be tailored to individual receptors. Given previous findings suggesting Notch1 is required for K-ras-induced tumorigenesis, we tested whether Notch1 is necessary for the development of mutant K-ras-driven NSCLC in vivo, by crossing the conditionally inducible K-rasG12D knock-in mouse model with a Notch1 conditional knockout mouse. In these mice, Cre-mediated recombination simultaneously activates the K-rasG12D allele and inactivates Notch1. We find that loss of Notch1 significantly reduced tumor initiation and overall tumor burden, indicating that Notch1 is required for K-ras-induced lung tumorigenesis. Moreover, our studies have shown that Notch1 contributes to K-ras-driven NSCLC by suppressing p53-mediated apoptosis. Importantly, these results identify the molecular basis for the documented correlation between Notch1 activity and poor prognosis in NSCLC patients having wild type p53, which represent 50% of all NSCLC cases. Based on our findings, we hypothesize that Notch1 is required for lung tumorigenesis via its ability to suppress p53, and that targeting Notch1 and/or its downstream effectors will inhibit the development and/or maintenance of NSCLC. The proposed studies will test this hypothesis and define the mechanisms underlying the requirement for Notch1 in K-Ras driven NSCLC. In addition, we will test the role of Notch1 in NSCLC driven by oncogenic events other than K-ras mutation, to determine if Notch1- directed therapies will provide benefit to a broad spectrum of NSCLC patients.