{"doi":"10.1101/2022.01.29.478337","title":"A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-X <sub>L</sub> Anti-apoptotic Protein in Kidney Cancer","abstract":"Abstract Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute’s Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1 , which encodes the BCL-X L anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-X L , but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-X L levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-X L dependence. Transcriptional profiling, however, identified a ‘BCL-X L dependency’ mRNA signature, which included elevated mesenchymal gene expression in BCL-X L dependent cells. Promoting mesenchymal transition increased BCL-X L dependence; whereas, conversion to a more differentiated state overcame BCL-X L dependence in kidney cancer cells. The ‘BCL-X L dependency’ mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-X L inhibitor, A-1331852, showed anti-tumor efficacy in vivo . Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-X L protein and justify further testing on BCL-X L blockade as a potential way to target a clinically aggressive subset of human kidney cancers. One Sentence Summary Cell state, but not pVHL and/or HIF status, defines the dependency of kidney cancer cells on the BCL-X L anti-apoptotic protein.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":300862,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":992142,"name":"Smruthi Maganti","orcid":null,"position":1,"is_corresponding":false},{"id":84471,"name":"John M. Krill-Burger","orcid":"0000-0001-9614-4671","position":2,"is_corresponding":false},{"id":650937,"name":"Cameron Fraser","orcid":"0000-0002-8180-5913","position":3,"is_corresponding":false},{"id":486065,"name":"Laura Stransky","orcid":"0000-0001-8834-936X","position":4,"is_corresponding":false},{"id":278920,"name":"Tomas Radivoyevitch","orcid":"0000-0002-9701-1851","position":5,"is_corresponding":false},{"id":650944,"name":"Kristopher A. Sarosiek","orcid":"0000-0002-4618-5085","position":6,"is_corresponding":false},{"id":58617,"name":"Francisca Vazquez","orcid":"0000-0002-2857-4685","position":7,"is_corresponding":false},{"id":63522,"name":"William G. Kaelin","orcid":"0000-0002-0574-4856","position":8,"is_corresponding":false},{"id":539441,"name":"Abhishek A. Chakraborty","orcid":"0000-0002-3382-188X","position":9,"is_corresponding":false},{"id":991793,"name":"Treg Grubb","orcid":"0000-0002-3388-758X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:57.812980Z","pmid":null,"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":[]}