Most notably, mTOR inhibits the process of autophagy whereby intracellular components are engulfed in double-membraned vesicles, the autophagosomes, which ultimately fuse with lysosomes where the contents are degraded and recycled into the cytosol 8. In a growth-promoting microenvironment, mTOR switches cell metabolism to increased production of protein, lipids and nucleotides, while suppressing catabolic pathways.
MTMR INHIBITOR DRIVER
The inherent genomic instability and phenotypic plasticity allow tumors to rapidly evolve and give rise to drug-resistant subclones as a cause of intrinsic or acquired therapy resistance and eventually lead to tumor relapse and therapy failure 1, 2, 3.Ī key driver of cancer drug resistance is the mTOR (mechanistic target of rapamycin) kinase, which acts in two distinct mTOR complexes, mTORC1 and mTORC2, to integrate a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic metabolism and cell growth 4, 5, 6, 7. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.Ĭancer therapy has improved significantly over the last decades, but ultimately still fails in almost half of all patients owing to the development of therapy resistance.
We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy.
Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes.
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