{"doi":"10.1101/2025.06.06.657881","title":"Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response","abstract":"Abstract Resistance to combination regimens containing the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively utilized agent. We previously established the anti-leukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supported leukemic survival and resistance to BH3 mimetics. Here, we report the anti-leukemic efficacy and mechanisms of co-targeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML dataset revealed a positive relationship between increased AC gene expression and venetoclax resistance. Targeting AC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was equipotent to the combination of venetoclax + cytarabine at reducing cell viability when evaluated ex vivo across a cohort of 71 primary AML patient samples. Mechanistically, SACLAC + venetoclax increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Collectively, these data demonstrate the efficacy of co-targeting AC and BCL-2 in AML and rationalize targeting AC as a therapeutic approach to overcome venetoclax resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":567720,"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":0.9614,"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":402541,"name":"Su‐Fern Tan","orcid":"0000-0002-8301-0823","position":1,"is_corresponding":false},{"id":410987,"name":"Jeremy J.P. 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Bishal Paudel","orcid":"0000-0002-5426-7048","position":11,"is_corresponding":false},{"id":355175,"name":"Irene Lee","orcid":"0000-0003-0004-6802","position":12,"is_corresponding":false},{"id":1098939,"name":"Bhavishya Ramamoorthy","orcid":null,"position":13,"is_corresponding":false},{"id":72659,"name":"Kevin A. Janes","orcid":"0000-0002-8028-6138","position":14,"is_corresponding":false},{"id":294642,"name":"Francine E. Garrett-Bakelman","orcid":"0000-0002-4771-628X","position":15,"is_corresponding":false},{"id":335375,"name":"Myles C. Cabot","orcid":null,"position":16,"is_corresponding":false},{"id":333399,"name":"Kelsey H. Fisher‐Wellman","orcid":"0000-0002-0300-829X","position":17,"is_corresponding":false},{"id":321068,"name":"Todd E. Fox","orcid":"0000-0001-5170-3951","position":18,"is_corresponding":false},{"id":402546,"name":"David F. Claxton","orcid":"0000-0001-9209-2405","position":19,"is_corresponding":false},{"id":489008,"name":"Charles E. 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