ArticleOncogene2018
PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 133 citations in OpenAlex.
- Poly(ADP-ribose) polymerase regulates transient receptor potential channel M2-dependent calpain activation in rd1 mouse retinal degeneration.Neural regeneration research · 2026Article
- TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer.Nature communications · 2026Article
- Dual PARP/Tankyrase Inhibition Enhances Antitumor Efficacy in PTEN-Deficient Endometrial Cancer.Journal of cellular and molecular medicine · 2026Article
- Novel fatty acid metabolism risk score model for guiding treatment in endometrial endometrioid cancer.Scientific reports · 2026Article
- Identification and Validation of a Novel Lactylation-related Gene Signature to Predict the Prognosis of Endometrial Cancer.Discover oncology · 2025Article
- Development of a machine learning model for predicting the expression of proteins associated with targeted therapy in endometrial cancer.Frontiers in oncology · 2025Article
- Phase II study of talazoparib in advanced cancers with BRCA1/2, DNA repair, and PTEN alterations.NPJ precision oncology · 2024Article
- Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer.Frontiers in oncology · 2024Review
- A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer.Cancer biology & therapy · 2023Article
- New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions.Cancer metastasis reviews · 2023Review
- Targeting DNA Damage Repair and Immune Checkpoint Proteins for Optimizing the Treatment of Endometrial Cancer.Pharmaceutics · 2023Review
- Article
- Synergistic effect of PARP inhibitor and BRD4 inhibitor in multiple models of ovarian cancer.Journal of cellular and molecular medicine · 2023Article
- Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).International journal of oncology · 2023Review
- Optimized detection of homologous recombination deficiency improves the prediction of clinical outcomes in cancer.NPJ precision oncology · 2022Article
- PTEN mutations as predictive marker for the high-grade endometrial cancer development in slovak women.Physiological research · 2022Article
- Article
- Growth arrest-specific transcript 5 represses endometrial cancer development by promoting antitumor function of tumor-associated macrophages.Cancer science · 2022Article
- Inhibition of BAD-Ser99 phosphorylation synergizes with PARP inhibition to ablate PTEN-deficient endometrial carcinoma.Cell death & disease · 2022Article
- CRISPR/Cas9 application in cancer therapy: a pioneering genome editing tool.Cellular & molecular biology letters · 2022Review
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising cancer therapeutics especially for tumors with deficient homologous recombination (HR) repair. However, as HR-deficient tumors represent only a small fraction of endometrial cancers, the therapeutic utility of PARP inhibitors is limited in this disease. Somatic loss of phosphatase and tensin homolog (PTEN), a tumor suppressor that counteracts phosphoinositide 3-kinase (PI3K) activity, is one of the most common genetic aberrations in endometrioid endometrial cancer. While previous works have identified the role of PTEN in DNA double-strand break repair, vulnerabilities of PTEN-deficient endometrioid endometrial cancers to PARP inhibition remain controversial. Here we find that PTEN-deficient endometrioid endometrial cancer cells are not responsive to PARP inhibitor Olaparib alone, but instead show superior sensitivity to compound inhibition with PI3K inhibitor BKM120, as evidenced by reduced clonogenic cell growth and three-dimensional (3D) spheroid disintegration. Mechanistically, PI3K blockade by BKM120 attenuated HR competency with γH2AX accumulation and reduced RAD51 and BRCA1 expression in Ishikawa, AN3CA and Nou-1 cells, but the same combination treatment led to enhanced phosphorylation of DNA-PK, a non-homologous end joining repair protein, in Hec-108 cells. Furthermore, we show that CRISPR/Cas9-mediated PTEN depletion rendered PTEN wild-type Hec-1A endometrioid endometrial cancer cells responsive to combined inhibition of PARP/PI3K, with concomitantly induced DNA damage accumulation and repair defects. The combination of BKM120 and Olaparib cooperated to inhibit tumor growth in a genetic mouse model of Pten-deficient endometrioid endometrial cancer. Together, these results suggest PI3K inhibition may be a plausible approach to expand the utility of PARP inhibitors to endometrioid endometrial cancers in a PTEN-deficient setting.
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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.