ArticleCancer letters2025
A PP2A-mtATR-tBid axis links DNA damage-induced CIP2A degradation to apoptotic dormancy and therapeutic resistance in PDAC.
Article in Cancer letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Osteogenic-like Phenotypic Reprogramming Is Associated with Reduced Malignant Behaviors in Pancreatic Cancer Cells Involving MAPK-ERK Signaling.International journal of molecular sciences · 2026Article
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- Analysis of the SH3-Domain Kinase Binding Protein 1 Predictive Model for Pancreatic Ductal Adenocarcinoma and CCCTC-Binding Factor Transcriptional Regulatory Study.World journal of oncology · 2025Article
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8 authors.
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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.
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