ArticleNPJ precision oncology2023
ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression.
Article in NPJ precision oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 18 citations in OpenAlex.
- DNA polymerase theta (Polθ): a novel candidate for targeted cancer therapy.Cancer biology & therapy · 2026Review
- Retinoic acid in health and disease.Signal transduction and targeted therapy · 2026Review
- Targeting a super-enhancer induced aldehyde dehydrogenase metabolic loop mitigates CDK4/6 inhibitor resistance in estrogen receptor-positive cancers.Nature communications · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- Combination therapy overcomes secondary PARPi resistance in ATM-deficient prostate cancer.NPJ precision oncology · 2025Article
- Targeting Multidrug Resistance in Cancer: Impact of Retinoids, Rexinoids, and Carotenoids on ABC Transporters.International journal of molecular sciences · 2025Review
- Reduced ALDH1A1 expression in multiple myeloma cells increases resistance to daratumumab via downregulation of retinoic acid.Cellular and molecular life sciences : CMLS · 2025Article
- BNIP3L/BNIP3-Mediated Mitophagy Contributes to the Maintenance of Ovarian Cancer Stem Cells.Journal of cellular and molecular medicine · 2025Article
- Targeting RAD52 overcomes PARP inhibitor resistance in preclinicalbioRxiv : the preprint server for biology · 2025Article
- Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids.Experimental and molecular pathology · 2025Article
- Clinical approaches to overcome PARP inhibitor resistance.Molecular cancer · 2025Review
- Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism.Journal of experimental & clinical cancer research : CR · 2025Article
- All-trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin.Molecular cancer therapeutics · 2025Article
- Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer.Frontiers in immunology · 2025Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- Polθ Inhibitor (ART558) Demonstrates a Synthetic Lethal Effect with PARP and RAD52 Inhibitors in Glioblastoma Cells.International journal of molecular sciences · 2024Article
- Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ.International journal of molecular sciences · 2024Review
- The mJournal of cancer research and clinical oncology · 2024Article
- Targeting the retinoic acid signaling pathway as a modern precision therapy against cancers.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated ovarian cancer lack the initial response to PARPi treatment, and the majority of those that initially respond eventually develop resistance. Our previous study has demonstrated that increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) contributes to PARPi resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) but the mechanism remains unknown. Here, we find that ALDH1A1 enhances the expression of DNA polymerase θ (Polθ, encoded by the POLQ gene) in ovarian cancer cells. Furthermore, we demonstrate that the retinoic acid (RA) pathway is involved in the transcription activation of the POLQ gene. The RA receptor (RAR) can bind to the retinoic acid response element (RARE) located in the promoter of the POLQ gene, promoting transcription activation-related histone modification in the presence of RA. Given that ALDH1A1 catalyzes the biosynthesis of RA, we conclude that ALDH1A1 promotes POLQ expression via the activation of the RA signaling pathway. Finally, using a clinically-relevant patient-derived organoid (PDO) model, we find that ALDH1A1 inhibition by the pharmacological inhibitor NCT-505 in combination with the PARP inhibitor olaparib synergistically reduce the cell viability of PDOs carrying BRCA1/2 mutation and positive ALDH1A1 expression. In summary, our study elucidates a new mechanism contributing to PARPi resistance in HR-deficient ovarian cancer and shows the therapeutic potential of combining PARPi and ALDH1A1 inhibition in treating these patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.