ArticleClinical cancer research : an official journal of the American Association for Cancer Research2019
PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 73 citations in OpenAlex.
- Gankyrin-mediated interaction between cancer cells and tumor-associated macrophages facilitates prostate cancer progression and androgen deprivation therapy resistance.Oncoimmunology · 2023Trial
- LDHC4 drives lung adenocarcinoma progression by inducing lactylation of RB1 at lysine 900 to disrupt the RB1-E2F1 complex.Journal of translational medicine · 2026Article
- Serotonin Modulates Lineage Plasticity in Neuroendocrine Prostate Cancer via Epigenetic Reprogramming.Cancer discovery · 2026Article
- Genomic landscape and precision therapy in prostate cancer: current status and future directions.NPJ precision oncology · 2026Review
- Advances in PARP Inhibition in Improving Outcomes of Breast Cancer, Ovarian Cancer, and Other Solid Tumors: Journey of Discovery, Development, and Clinical Updates of Talazoparib.Drug design, development and therapy · 2026Review
- Mechanistic insights and molecular therapy for neuroendocrine prostate cancer.Frontiers in oncology · 2026Review
- The Quartet of Core Oncogenic Drivers in Neuroendocrine Prostate Cancer: Multi-Omics Dataset Integration to Forge a Translational Link Between Biology and Precision Therapy.International journal of biological sciences · 2026Review
- Patient-derived xenograft models: Current status, challenges, and innovations in cancer research.Genes & diseases · 2025Review
- Widespread activation and critical role of EMT and stemness in the neuroendocrine differentiation of prostate cancer (Review).Oncology reports · 2025Review
- Myc family proteins: Molecular drivers of tumorigenesis and resistance in neuroendocrine tumors.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- RSK1-driven TRIM28/E2F1 feedback loop promotes castration-resistant prostate cancer progression.The Journal of clinical investigation · 2025Article
- New Insights into Potential Therapeutic Targets for Neuroendocrine Prostate Cancer: From Bench to Clinic.Research (Washington, D.C.) · 2025Review
- Engineering of layer-by-layer acetate-coated paclitaxel loaded poly(lactide-co-glycolide) acid nanoparticles for prostate cancer therapy- in vitro.Journal of pharmaceutical sciences · 2024Article
- Unraveling molecular characteristics and tumor microenvironment dynamics of neuroendocrine prostate cancer.Journal of cancer research and clinical oncology · 2024Review
- Neuroendocrine transdifferentiation in human cancer: molecular mechanisms and therapeutic targets.MedComm · 2024Review
- Article
- PARP-ish: Gaps in Molecular Understanding and Clinical Trials Targeting PARP Exacerbate Racial Disparities in Prostate Cancer.Cancer research · 2024Review
- Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Regulation of Molecular Biomarkers Associated with the Progression of Prostate Cancer.International journal of molecular sciences · 2024Review
- Structural insights into the ubiquitylation strategy of the oligomeric CRL2The EMBO journal · 2024Article
Corrections and comments
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
Abstract
purposeIn this study, we addressed the underlying mechanisms for the association between enzalutamide (ENZ) treatment and neuroendocrine prostate cancer (NEPC), and the critical involvement of MYCN, and loss of RB1 function in neuroendocrine differentiation (NED) of prostatic epithelial cells, and the development of NEPC. We further sought to determine whether PARP inhibition could suppress NEPC, and to identify molecular determinants of this therapeutic activity. EXPERIMENTAL
designWe used a novel prostate cancer patient-derived xenograft (PDX) treatment model, prostatic adenocarcinoma and NEPC cell lines, an NEPC organoid line, and NEPC xenograft models to address the mechanistic basis of ENZ-induced NED, and to analyze suppression of NED and NEPC growth by PARP inhibition.
resultsWe identified an ENZ treatment-associated glucocorticoid receptor (GR)-MYCN-CDK5-RB1-E2F1 signaling pathway that drives NED in prostatic adenocarcinoma PDX and cell line models. Mechanistically, long-term ENZ treatment transcriptionally upregulates signaling of the GR-MYCN axis, leading to CDK5R1 and CDK5R2 upregulation, Rb1 phosphorylation, and N-Myc-mediated and E2F1-mediated NED gene expression. Importantly, olaparib (OLA) or talazoparib (TALA) suppressed these activities, and the combination of OLA and dinaciclib (DINA), an inhibitor of CDK2 and CDK5, which also inhibits Rb1 phosphorylation, suppressed NED and significantly improved therapeutic efficiency in NEPC cells
conclusionsThe results of our study indicate an important role of GR-MYCN-CDK5R1/2-RB1-NED signaling in ENZ-induced and PARP inhibitor-suppressed NEPC. We also demonstrated efficacy for OLA+DINA combination therapy in NEPC xenograft models.
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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.