{"doi":"10.1002/1878-0261.70124","title":"Inhibition of <scp>CDK</scp> 9 enhances <scp>AML</scp> cell death induced by combined venetoclax and azacitidine","abstract":"Relapsed/refractory (R/R) disease is a major hurdle to long-term survival of acute myeloid leukemia (AML) patients treated with intensive cytarabine (AraC)-based chemotherapy. R/R AML salvage treatment with venetoclax (VEN) + azacitidine (AZA) results in overall response rates between 20% and 60%, and responses are not durable, highlighting the need for new therapies. Here, we report elevated mTORC1 signaling in AraC-resistant AML cell lines, primary AML patient samples, and patient-derived xenograft (PDX) AML cells derived from patients at relapse postchemotherapy. The CDK9 inhibitor AZD4573 suppresses mTORC1 signaling and downregulates c-MYC and MCL-1, inducing AraC-resistant AML cell death. AZD4573 in combination with VEN + AZA significantly increases AML cell death compared to any of the two-drug combinations and suppresses AML progenitor cells but spares normal hematopoietic progenitor cells. The efficacy of this triple combination remains even with a 10-fold reduction of VEN concentration. The roles of MCL-1 and c-MYC in the three-drug combination were confirmed by knockdown. This study demonstrates that AZD4573 enhances the activity of VEN + AZA against AraC-resistant AML by downregulating c-MYC and MCL-1 and to a lesser extent cellular respiration.","journal":"Molecular Oncology","year":2025,"id":575000,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"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":1070285,"name":"Jianlei Zhao","orcid":null,"position":1,"is_corresponding":false},{"id":1483028,"name":"Aaban Asfar Azmi","orcid":null,"position":2,"is_corresponding":false},{"id":1482591,"name":"Avanti Gupte","orcid":"0000-0002-3235-6111","position":3,"is_corresponding":false},{"id":1235724,"name":"Jenna Thibodeau","orcid":null,"position":4,"is_corresponding":false},{"id":1482592,"name":"Shuang Liu","orcid":"0000-0001-6306-6929","position":5,"is_corresponding":false},{"id":1483029,"name":"Jinli Yang","orcid":null,"position":6,"is_corresponding":false},{"id":899848,"name":"Guan Wang","orcid":"0000-0002-7432-7933","position":7,"is_corresponding":false},{"id":312974,"name":"Holly Edwards","orcid":null,"position":8,"is_corresponding":false},{"id":301316,"name":"Lisa Polin","orcid":"0000-0002-9189-055X","position":9,"is_corresponding":false},{"id":311237,"name":"Juiwanna Kushner","orcid":"0009-0006-9880-8703","position":10,"is_corresponding":false},{"id":311238,"name":"Sijana H. Dzinic","orcid":"0009-0000-7543-694X","position":11,"is_corresponding":false},{"id":312975,"name":"Kathryn White","orcid":null,"position":12,"is_corresponding":false},{"id":264008,"name":"Julie L. Boerner","orcid":"0000-0003-1711-4998","position":13,"is_corresponding":false},{"id":246010,"name":"Maik Hüttemann","orcid":"0000-0001-6310-7081","position":14,"is_corresponding":false},{"id":350221,"name":"Jay Yang","orcid":"0000-0003-0790-7951","position":15,"is_corresponding":false},{"id":1482593,"name":"Yue Wang","orcid":"0000-0003-4960-2208","position":16,"is_corresponding":false},{"id":311240,"name":"Jeffrey W. Taub","orcid":"0000-0003-2228-3235","position":17,"is_corresponding":false},{"id":311241,"name":"Yubin Ge","orcid":"0000-0002-8748-716X","position":18,"is_corresponding":false},{"id":1220932,"name":"Shuangshuang Wu","orcid":"0000-0003-1899-1474","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:57:44.572630Z","pmid":"40955793","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":[]}