Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. 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. 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.

癌细胞具有特征性的代谢，主要是由信号转导网络的改变而不是代谢酶的突变引起的。对于具有癌症选择性的代谢药物，需要确定赋予可药物脆弱性的信号改变。在这里，我们证明了许多具有获得性癌症耐药性的肿瘤细胞对不同的癌症代谢抑制剂的敏感性增加。我们证明这种代谢脆弱性是由 mTORC1 驱动的，mTORC1 促进对化疗和靶向癌症药物的抵抗，但同时抑制自噬。我们表明自噬对于肿瘤细胞应对治疗性代谢紊乱至关重要，并且 mTORC1 介导的自噬抑制是必要的，并且足以产生导致能量危机和细胞凋亡的代谢脆弱性。我们的研究将 mTOR 诱导的癌症耐药性与自噬缺陷联系起来，作为代谢倾向的一个原因，并为其他治疗难治性肿瘤患者的治疗打开了治疗窗口。