DeBerardinis, Ralph J.2021-09-172021-09-172019-082019-07-31August 201https://hdl.handle.net/2152.5/9628Behind heart disease, cancer is the leading cause of death today in Americans. Among cancers, lung cancer is the deadliest, killing as many individuals as next 3 most lethal cancer types combined. Approximately 80% of lung cancers are a type known as non-small cell lung cancer (NSCLC), and despite numerous advances in the treatment of NSCLC, only 18% of all NSCLC patients live 5 years after their initial diagnosis. To identify new therapeutic targets in NSCLC, we performed a viability-based RNA interference (RNAi) screen targeting nuclear receptors, their coregulators and chromatin remodelers. This screen identified RUVBL1 and RUVBL2 (collectively referred to as RUVBL1/2) as differentially required for the viability of NSCLC. We show that RUVBL1/2 require their ATPase activity to support NSCLC viability and have developed an orally bioavailable, potent and specific inhibitor of RUVBL1/2 ATPase activity, known as Compound B. Multiple unbiased analyses suggested that RUVBL1/2 may have roles in DNA replication in NSCLC, and inhibition or depletion of RUVBL1/2 in sensitive NSCLC lines delays S-phase progression and ultimately results in cancer cell death via replication catastrophe. While Compound B treatment in vivo produces modest anti-tumor activity, only a subset of NSCLC cell lines show a therapeutically meaningful response. To enhance the efficacy of Compound B, we searched for therapies that may synergize with Compound B. Various analyses indicated that RUVBL1/2 may have roles in the response to ionizing radiation (IR), and indeed, genetic depletion or pharmacological inhibition of RUVBL1/2 radiosensitized NSCLC cell lines and patient tumors both in vitro and in vivo. Interestingly, Compound B, did not radiosensitize models of non-transformed cells, potentially because key DNA damage proteins such as ATM and DNA-PKcs were more stable after Compound B treatment in normal cells than in tumor cells. The combined necessity of RUVBL1/2 for NSCLC viability and the recovery from radiation, specifically in tumor cells, make RUVBL1/2 an attractive target for future preclinical development as a radiosensitizer in NSCLC.application/pdfenCarcinoma, Non-Small-Cell LungCarrier ProteinsDNA HelicasesDNA RepairLung NeoplasmsThesis2021-09-171268338270