{"doi":"10.64898/2025.12.10.693422","title":"BCL-X <sub>L</sub> Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers","abstract":"Abstract The BCL-X L anti-apoptotic protein is a clear cell Renal Cell Carcinoma (ccRCC) dependency; however, the mechanism of this dependence and its relevance in other aggressive kidney cancer contexts, including metastatic and/or rare RCC subtypes [e.g., Fumarate Hydratase (FH)-deficient and sarcomatoid RCCs], is unknown. Computational predictions, using a machine learning model trained on the human RCC TCGA dataset, and cell-based validations, confirmed BCL-X L dependence in all RCC subtypes. Remarkably, cell state changes, ‘anoikis’ programs, inflammatory state, and metabolic perturbations (e.g., fumarate production in FH-deficient RCCs) independently conferred increased BCL-X L dependence. Correlation studies revealed that increased AMPK isoform 2 ( PRKAA2 ) expression is a kidney-specific biomarker of BCL-X L dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-X L blockade. Finally, using functional studies, we developed a multivariate model that accurately predicted BCL-X L dependence in RCC. Our studies offer biomarkers for patient stratification and credential BCL-X L as a subtype agnostic vulnerability in difficult-to-treat RCCs.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559698,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9685,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991793,"name":"Treg Grubb","orcid":"0000-0002-3388-758X","position":1,"is_corresponding":false},{"id":656964,"name":"Ananthan Sadagopan","orcid":"0000-0001-6306-4907","position":2,"is_corresponding":false},{"id":650938,"name":"Xingping Qin","orcid":"0000-0003-3263-0843","position":3,"is_corresponding":false},{"id":1461808,"name":"Kylee Madison","orcid":null,"position":4,"is_corresponding":false},{"id":1461809,"name":"Autumn Hall","orcid":null,"position":5,"is_corresponding":false},{"id":256163,"name":"Belinda Willard","orcid":"0000-0001-6884-6369","position":6,"is_corresponding":false},{"id":852778,"name":"Sakari Vanharanta","orcid":"0000-0001-5619-7963","position":7,"is_corresponding":false},{"id":650944,"name":"Kristopher A. Sarosiek","orcid":"0000-0002-4618-5085","position":8,"is_corresponding":false},{"id":567170,"name":"Srinivas R. Viswanathan","orcid":"0000-0003-1856-3023","position":9,"is_corresponding":false},{"id":539441,"name":"Abhishek A. Chakraborty","orcid":"0000-0002-3382-188X","position":10,"is_corresponding":false},{"id":340733,"name":"Tupa Basuroy","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:39.010633Z","pmid":"41415469","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":[]}