ArticleOncotarget2015
Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 48 citations in OpenAlex.
- mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review.Targeted oncology · 2017Pooled it
- Intermittent Fasting and Androgen Receptor Signaling in Prostate Cancer: Metabolic Crosstalk and Therapeutic Implications.International journal of molecular sciences · 2026Review
- Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Review
- Extracellular vesicle-mediated delivery of CRISPR machinery silences androgen receptor in castration-resistant prostate cancer cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- HER2 as a molecular trojan horse in prostate cancer: mechanistic insights and therapeutic unlocks.Molecular biology reports · 2025Review
- Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.Journal of pharmaceutical analysis · 2025Review
- Understanding Enzalutamide-Resistance Based on a Functional Single-Cell Approach.The Prostate · 2025Article
- GPCR-Gα13 Involvement in Mitochondrial Function, Oxidative Stress, and Prostate Cancer.International journal of molecular sciences · 2024Review
- Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis.Molecular oncology · 2024Article
- Review
- Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment.International journal of molecular sciences · 2023Review
- Anti-Androgenic Therapies Targeting the Luminal Androgen Receptor of a Typical Triple-Negative Breast Cancer.Cancers · 2022Review
- Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer.Cancers · 2022Review
- The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.Nature communications · 2022Article
- Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors.Nature communications · 2022Article
- (+)-JJ-74-138 is a Novel Noncompetitive Androgen Receptor Antagonist.Molecular cancer therapeutics · 2022Article
- Diosmetin Induces Modulation of Igf-1 and Il-6 Levels to Alter Rictor-Akt-PKCα Cascade in Inhibition of Prostate Cancer.Journal of clinical medicine · 2021Article
- Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer.The Journal of clinical investigation · 2021Article
- Article
- The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP 'MDV-R') and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP 'PF-R'). MTS analysis showed that LNCaP 'PF-R' was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP 'MDV-R' was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP 'MDV-R' cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP 'PF-R' cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC 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.