ArticleScience advances2025
Uncoupling of Akt and mTOR signaling drives resistance to Akt inhibition in PTEN loss prostate cancers.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Genetic Ablation and Multi-Omics Profiling Reveal CEP55 as a Key Driver of Tumorigenesis in Diverse Cancer Models.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Light-driven thermotropic hydrogel with nanomodulator enables lipid intervention and cavity delivery for postsurgical tumor therapy.Cell reports. Medicine · 2026Article
- Osteocyte-Derived GDF15 Promotes Paclitaxel Resistance, Tumor Growth, and Bone Microenvironment Regulation in Prostate Cancer.Current issues in molecular biology · 2026Article
- Targeting arginine metabolism overcomes chemotherapy resistance in aggressive-variant prostate cancers.iScience · 2026Article
- Key Molecular Events in PMCells · 2026Article
- WTAP stabilized by USP7 contributes to enzalutamide resistance in prostate cancer via mediating AKT mCancer gene therapy · 2026Article
- Glyoxalase 2 Drives D-Lactate Oncometabolite Signaling to Promote Prostate Cancer Aggressiveness via FAK/Src Activation.Antioxidants (Basel, Switzerland) · 2026Article
- 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
- Overcoming Immune Evasion in the Prostate Tumor Microenvironment: Novel Targeted Strategies to Improve Treatment Outcomes.Cancers · 2025Review
- Potential repurposing of lapatinib and pazopanib as neuroprotective agents in a rat model of Huntington's disease.Inflammopharmacology · 2025Article
- PTEN defects in cancer, from gene to protein molecular causes and therapeutic targets.Discover oncology · 2025Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Recent phase 3 clinical trial showed improved radiographic progression-free survival in PTEN-deficient prostate cancers treated with combined Akt and AR inhibition. Building on this and our previous research into PI3K and AR signaling interactions, we aimed to define the mechanisms of response and resistance to Akt inhibition. We discovered that restoration of mTOR signaling was the early dominant driver of resistance to Akt inhibition. Mechanistically, this can be achieved through molecular alterations, resulting in loss of negative regulators of mTOR. Unexpectedly, we discovered that this was dominated by restoration of mTOR signaling through the nutrient sensing arm. This can be achieved by loss of the components of the GATOR/KICSTOR complexes or through cellular processes, leading to the recycling of amino acids. The addition of an mTOR inhibitor restored sensitivity to Akt inhibition and represents a precision-based strategy to overcome resistance in the clinic.
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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.