Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021,USA.
Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
Endocrinology. 2022 Jun 1;163(6). doi: 10.1210/endocr/bqac041.
The mechanistic target of the rapamycin (mTOR) signaling pathway is the central regulator of cell growth and proliferation by integrating growth factor and nutrient availability. Under healthy physiological conditions, this process is tightly coordinated and essential to maintain whole-body homeostasis. Not surprisingly, dysregulated mTOR signaling underpins several diseases with increasing incidence worldwide, including obesity, diabetes, and cancer. Consequently, there is significant clinical interest in developing therapeutic strategies that effectively target this pathway. The transition of mTOR inhibitors from the bench to bedside, however, has largely been marked with challenges and shortcomings, such as the development of therapy resistance and adverse side effects in patients. In this review, we discuss the current status of first-, second-, and third-generation mTOR inhibitors as a cancer therapy in both preclinical and clinical settings, with a particular emphasis on the mechanisms of drug resistance. We focus especially on the emerging role of diet as an important environmental determinant of therapy response, and posit a conceptual framework that links nutrient availability and whole-body metabolic states such as obesity with many of the previously defined processes that drive resistance to mTOR-targeted therapies. Given the role of mTOR as a central integrator of cell metabolism and function, we propose that modulating nutrient inputs through dietary interventions may influence the signaling dynamics of this pathway and compensatory nodes. In doing so, new opportunities for exploiting diet/drug synergies are highlighted that may unlock the therapeutic potential of mTOR inhibitors as a cancer treatment.
雷帕霉素（mTOR）信号通路的作用机制是通过整合生长因子和营养可用性来调节细胞生长和增殖的中央调节剂。在健康的生理条件下，这个过程是紧密协调的，对于维持全身的平衡至关重要。毫不奇怪，mTOR 信号通路的失调是全球发病率不断上升的多种疾病的基础，包括肥胖、糖尿病和癌症。因此，开发有效靶向该途径的治疗策略具有重要的临床意义。然而，mTOR 抑制剂从实验室到临床的转变在很大程度上受到了挑战和缺陷的困扰，例如治疗耐药性的发展和患者的不良反应。在这篇综述中，我们讨论了第一代、第二代和第三代 mTOR 抑制剂作为癌症治疗在临床前和临床环境中的现状，特别强调了耐药机制。我们特别关注饮食作为治疗反应的重要环境决定因素的新兴作用，并提出了一个概念框架，将营养可用性和肥胖等全身代谢状态与许多先前定义的驱动 mTOR 靶向治疗耐药的过程联系起来。鉴于 mTOR 作为细胞代谢和功能的中央整合因子的作用，我们提出通过饮食干预来调节营养输入可能会影响该途径和补偿节点的信号动态。这样，就突出了利用饮食/药物协同作用的新机会，这可能会释放 mTOR 抑制剂作为癌症治疗的治疗潜力。
