{"doi":"10.1016/j.canlet.2025.217790","title":"A PP2A-mtATR-tBid axis links DNA damage-induced CIP2A degradation to apoptotic dormancy and therapeutic resistance in PDAC","abstract":"DNA damage-based drugs are widely used in cancer therapy, yet resistance remains a major challenge. In this study, we uncovered a non-DNA repair mechanism contributing to resistance in pancreatic ductal adenocarcinoma (PDAC). We show that in gemcitabine-resistant PDAC cells, CIP2A undergoes ubiquitin-mediated degradation, resulting in enhanced PP2A phosphatase activity. This leads to the dephosphorylation of ATR at Ser428 in the cytoplasm, promoting the formation of the prolyl cis-isomeric form of ATR at its Ser428-Pro429 motif. The resulting cis-ATR functions as a mitochondria-targeted antiapoptotic protein (mtATR). Surprisingly, resistant PDAC cells paradoxically accumulated both mtATR and proapoptotic tBid at the mitochondria, forming a stable mtATR-tBid complex that induces a state of apoptotic dormancy. Disrupting this complex, either with the PP2A inhibitor LB-100 or a cytoplasmic ATR-specific antibody, reactivates the pre-accumulated tBid and restores apoptosis in resistant PDAC cells. In an orthotopic PDAC mouse model, LB-100 alone significantly inhibit gemcitabine-resistant tumor growth by disrupting the mtATR-tBid complex. These findings reveal a previously unrecognized mechanism of resistance to DNA damage-based therapies and identify a novel action mechanism of LB-100, characterized by the CIP2A degradation-mediated PP2A-mtATR-tBid axis. By targeting mtATR-tBid-mediated apoptotic dormancy, this strategy offers a promising approach to restore apoptotic sensitivity in drug-resistant cancers.","journal":"Cancer Letters","year":2025,"id":544142,"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":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":418922,"name":"Himadri Biswas","orcid":null,"position":1,"is_corresponding":false},{"id":361840,"name":"Yetunde Makinwa","orcid":"0000-0001-9452-8233","position":2,"is_corresponding":false},{"id":398619,"name":"Shi‐He Liu","orcid":null,"position":3,"is_corresponding":false},{"id":1401189,"name":"Zizheng Dong","orcid":"0000-0003-4521-1736","position":4,"is_corresponding":false},{"id":1344793,"name":"Jing-Yuan Liu","orcid":"0000-0002-8289-5834","position":5,"is_corresponding":false},{"id":445464,"name":"Jian‐Ting Zhang","orcid":"0000-0002-2803-9914","position":6,"is_corresponding":false},{"id":1433969,"name":"Yue Zou","orcid":"0000-0003-2780-9443","position":7,"is_corresponding":false},{"id":833868,"name":"Yibo Luo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:08.338070Z","pmid":"40354992","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":[]}