{"doi":"10.1126/sciadv.aay9131","title":"Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells","abstract":"Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.","journal":"Science Advances","year":2020,"id":96011,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476594,"name":"Ji Su Lee","orcid":"0000-0002-3569-217X","position":1,"is_corresponding":false},{"id":262629,"name":"Jiamin Zhang","orcid":"0000-0001-5919-002X","position":2,"is_corresponding":false},{"id":476595,"name":"Sungbin Choi","orcid":"0000-0002-2472-6944","position":3,"is_corresponding":false},{"id":476596,"name":"Žarko Bošković","orcid":"0000-0001-9376-527X","position":4,"is_corresponding":false},{"id":476597,"name":"Ran Zhao","orcid":"0000-0003-3390-5343","position":5,"is_corresponding":false},{"id":476598,"name":"Mengqiu Song","orcid":"0000-0003-1249-9876","position":6,"is_corresponding":false},{"id":285774,"name":"Rui Wang","orcid":"0000-0003-3825-3620","position":7,"is_corresponding":false},{"id":476599,"name":"Jie Tian","orcid":"0000-0002-9681-1523","position":8,"is_corresponding":false},{"id":411363,"name":"Mee‐Hyun Lee","orcid":"0000-0002-1216-0218","position":9,"is_corresponding":false},{"id":476600,"name":"Jae Hwan Kim","orcid":"0000-0001-9775-165X","position":10,"is_corresponding":false},{"id":476601,"name":"Minju Jeong","orcid":"0000-0003-0777-102X","position":11,"is_corresponding":false},{"id":476602,"name":"Jung‐Hyun Lee","orcid":"0000-0002-9662-1703","position":12,"is_corresponding":false},{"id":476603,"name":"Michael Petukhov","orcid":"0000-0003-3771-1343","position":13,"is_corresponding":false},{"id":235912,"name":"Sam W. Lee","orcid":"0000-0002-4114-7338","position":14,"is_corresponding":false},{"id":295485,"name":"Sang Gyun Kim","orcid":"0000-0001-9548-2425","position":15,"is_corresponding":false},{"id":251222,"name":"Lee Zou","orcid":"0000-0003-3094-1058","position":16,"is_corresponding":false},{"id":476604,"name":"Sanguine Byun","orcid":"0000-0003-3903-5887","position":17,"is_corresponding":false},{"id":476593,"name":"Seung Ho Shin","orcid":"0000-0002-2694-3889","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T22:34:34.781847Z","pmid":"32789167","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}