Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition

M Dermit,R Unwin,H Campbell,J G Gribben,P Casado,D E Foxler,V Rajeeve,T V Sharp,P R Cutillas,E H Wilkes,S Critchlow

doi:10.1038/onc.2016.435

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.

Highlights

Phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling has key roles in the regulation of cell growth, survival, motility and bioenergetic metabolism, and it is one of the most frequently mutated pathways in cancer.[1]
The drug holiday strategy has been successfully used to overcome resistance in melanoma, chronic myeloid leukemia and lung cancer cells treated with the kinase inhibitors vemurafenib, imatinib and erlotinib, respectively.[5,6,7]
We found that reactive oxygen species (ROS) were produced in a mammalian target of rapamycin complex 1-dependent, but AKT-independent, manner and mediated glycolytic activity via hypoxia-inducible factor (HIF), but not c-MYC

Summary

Introduction

Phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling has key roles in the regulation of cell growth, survival, motility and bioenergetic metabolism, and it is one of the most frequently mutated pathways in cancer.[1] small-molecule inhibitors targeting the PI3K pathway are being developed at a rapid pace, and both preclinical and early clinical studies are beginning to suggest strategies for their effective therapeutic use.[2] Experience with other successful targeted agents, suggests that resistance is likely to reduce the durability of any clinical benefit.[3,4]. The proliferative disadvantage suffered by resistant cells in the absence of drug is considered as a key event for the success of this strategy.[6] The molecular mechanisms that give rise to this deficit in proliferation are poorly understood, and a better knowledge could be used to develop strategies to improve the response of patients treated with signaling inhibitors

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