title: Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.
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.
authors.affiliation: Cell Signalling & Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Dermit
authors.affiliation: Cell Signalling & Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Casado
authors.affiliation: Cell Signalling & Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Rajeeve
authors.affiliation: Cell Signalling & Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: E H
authors.initials: EH
authors.lastname: Wilkes
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: D E
authors.initials: DE
authors.lastname: Foxler
authors.affiliation: AstraZeneca, Oncology iMED, Cheshire, UK.
authors.forename: H
authors.initials: H
authors.lastname: Campbell
authors.affiliation: AstraZeneca, Oncology iMED, Cheshire, UK.
authors.forename: S
authors.initials: S
authors.lastname: Critchlow
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: T V
authors.initials: TV
authors.lastname: Sharp
authors.affiliation: Cancer Immunology Group, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: J G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: UCL Centre for Nephrology, Royal Free Campus and Hospital, University College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Unwin
authors.affiliation: Cell Signalling & Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Cutillas
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases