{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/9628"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/9628","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"The Role of RUVBL1/RUVBL2 and Their Potential as Therapeutic Targets in Non-Small Cell Lung Cancer","abstract":"Behind 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.","abstract_html":"Behind 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.","abstract_has_math":false,"creators":["Yenerall, Paul Matthew, II"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["DeBerardinis, Ralph J.","Minna, John D.","Kittler, Ralf","Mangelsdorf, David J.","Kraus, W. Lee"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-09-17T18:00:02Z","date_published":"2021-09-17T18:00:02Z","updated_at":"2026-07-24T05:52:29Z","subjects":["Carcinoma, Non-Small-Cell Lung","Carrier Proteins","DNA Helicases","DNA Repair","Lung Neoplasms"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1268338270"],"render_values":[{"text":"1268338270","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/9628","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["DeBerardinis, Ralph J.","Minna, John D.","Kittler, Ralf","Mangelsdorf, David J.","Kraus, W. 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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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The Role of RUVBL1/RUVBL2 and Their Potential as Therapeutic Targets in Non-Small Cell Lung Cancer"]}]}],"canonical_facts":{"dc:contributor":["DeBerardinis, Ralph J.","Minna, John D.","Kittler, Ralf","Mangelsdorf, David J.","Kraus, W. Lee"],"dc:creator":["Yenerall, Paul Matthew, II"],"dc:date":["2021-09-17T18:00:02Z","2019-08","2019-07-31","August 2019"],"dc:description":["Behind 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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/9628","1268338270"],"dc:language":["en"],"dc:subject":["Carcinoma, Non-Small-Cell Lung","Carrier Proteins","DNA Helicases","DNA Repair","Lung Neoplasms"],"dc:title":["The Role of RUVBL1/RUVBL2 and Their Potential as Therapeutic Targets in Non-Small Cell Lung Cancer"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:29Z"}