ArticleMolecular cancer therapeutics2023
Small-Molecule-Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death.
Article in Molecular cancer therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers.International journal of molecular sciences · 2026Review
- Ciliated Cells Drive Critical STING-Mediated Tumor Suppression in the Fallopian Tube Epithelium.Cancer research · 2026Article
- Natural Product Target Identification of Wheldone, a Fungal Metabolite, as a KIF11 Inhibitor in Ovarian Cancer Using the DiffPOP (Differential Protein Precipitation) Method.Molecular & cellular proteomics : MCP · 2026Article
- The role of PPP2R1A variants in gynecologic malignancies: a paradigm shift in immuno-oncology.Journal of translational medicine · 2026Review
- The protein phosphatase 2A-B56α complex regulates N-Myc degradation in neuroblastoma.The Journal of biological chemistry · 2026Article
- Understanding the Functional Dependence and Inhibition of the Bcl‑2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine.ACS pharmacology & translational science · 2025Article
- Emerging roles of the cancerous inhibitor of protein phosphatase 2A (CIP2A) in ovarian cancer.Scientific reports · 2025Article
- Identification of a TNIK-CDK9 Axis as a Targetable Strategy for Platinum-Resistant Ovarian Cancer.Molecular cancer therapeutics · 2025Article
- Characterization of RNF144B and PPP2R2A identified by a novel approach using TCGA data in ovarian cancer.Scientific reports · 2025Article
- KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.Oncogene · 2024Article
- Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.Cell death and differentiation · 2024Article
- Article
- TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- KRAS-mediated upregulation of CIP2A promotes suppression of PP2A-B56α to initiate pancreatic cancer development.bioRxiv : the preprint server for biology · 2024Article
- Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway.Research square · 2024Article
- Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.NPJ genomic medicine · 2024Article
- A strategy to disentangle direct and indirect effects on (de)phosphorylation by chemical modulators of the phosphatase PP1 in complex cellular contexts.Chemical science · 2024Article
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer.Cell & bioscience · 2023Article
- PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis.The Journal of clinical investigation · 2023Article
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Authors and funding
23 authors at 7 institutions in 1 country.
Funding
Abstract
High-grade serous carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP inhibitors (PARPi) have become the mainstay of HGSC-targeted therapy, given that these tumors are driven by a high degree of genomic instability (GI) and homologous recombination (HR) defects. Nonetheless, approximately 30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a small-molecule activator of protein phosphatase 2A (PP2A; SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in patient-derived HGSC cells and xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56α, B56γ, and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061-induced stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient HGSC cells and PDX models. Our studies identify PP2A as a novel regulator of HR and indicate PP2A modulators as a therapeutic therapy for HGSC. In summary, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi resistance driven by BRCA1/2 mutation reversions.
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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.