ArticleOncogene2017
Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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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
21 citing papers in PubMed, 33 citations in OpenAlex.
- Inhibition of the PI3K signaling pathway in cancer cells by Agrimonia eupatoria L. ethanolic extract: identification of tricoumaroyl spermidine as a potential PI3K inhibitor.BMC complementary medicine and therapies · 2026Article
- Presbycusis: Pathology, Signal Pathways, and Therapeutic Strategy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- A case of acute promyelocytic leukemia complicated by mitochondrial disease.International journal of hematology · 2025Article
- Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells.Cell communication and signaling : CCS · 2025Article
- Insights into the gut microbiome-metabolite dynamics in breast cancer.Gut microbes reports · 2025Review
- Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.Science advances · 2024Article
- The PI3K/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer.International journal of biological sciences · 2024Review
- Folate conjugated nanomedicines for selective inhibition of mTOR signaling in polycystic kidneys at clinically relevant doses.Biomaterials · 2023Article
- Article
- Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Principles of phosphoproteomics and applications in cancer research.The Biochemical journal · 2023Article
- Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.Antioxidants (Basel, Switzerland) · 2022Article
- Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes.Cell death & disease · 2021Article
- SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer.International journal of molecular sciences · 2021Article
- Autophagy, One of the Main Steps in Periodontitis Pathogenesis and Evolution.Molecules (Basel, Switzerland) · 2020Review
- Oral Mucositis: An Update on Innate Immunity and New Interventional Targets.Journal of dental research · 2020Review
- Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer.Cancers · 2019Article
- Improvement in Impaired Social Cognition but Not Seizures by Everolimus in a Child with Tuberous Sclerosis-Associated Autism through Increased Serum Antioxidant Proteins and Oxidant/Antioxidant Status.Case reports in pediatrics · 2019Article
- Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.The Journal of clinical investigation · 2018Article
- Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer.Frontiers in oncology · 2018Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α. This metabolic imbalance was reversed by mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Interestingly, neither AKT nor c-MYC was involved in mediating the metabolic phenotype, despite the latter contributing to resistant cells' proliferation. These data suggest that an AKT-independent PI3K/mTORC1 axis operates in these cells. The excessive ROS hampered cell division, and the metabolic phenotype made resistant cells more sensitive to hydrogen peroxide and nutrient starvation. Thus, the proliferative defect of PI3Ki-resistant cells during drug holidays is caused by defective metabolic adaptation to chronic PI3K/mTOR pathway inhibition. This metabolic imbalance may open the therapeutic window for challenge with metabolic drugs during drug holidays.
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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.