The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells.

中文翻译：

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GSK3信号与mTOR网络的串扰及其对癌症靶向治疗的影响。

针对特定的促肿瘤致癌或非致癌信号通路的治疗药物的引入彻底改变了癌症的治疗方法。雷帕霉素（mTOR）的机械靶标（mTOR）是高度保守的Ser / Thr激酶，是磷脂酰肌醇3激酶（PI3K）/ Akt / mTOR网络的中心枢纽，它是癌症中最常失控的信号传导途径之一，这使其成为有吸引力的治疗靶标。许多mTOR抑制剂已进入临床试验，其中两种已被正式批准为抗癌治疗剂。但是，靶向mTOR的药物在癌症患者中获得的成功非常有限。通常，成功针对癌症进行靶向治疗的主要障碍是耐药性，从治疗的一开始（先天性抵抗力）或最初的反应后开始，以及经过反复的药物治疗（逃避或获得性抵抗力）。耐药性导致治疗失败和疾病的复发/发展。对mTOR抑制剂的抗药性除其他原因外，还取决于几种信号通路的激活/失活，这些信号通路包括由糖原合酶激酶3（GSK3）调节的信号，该蛋白靶向其库中的大量底物，从而协调了许多过程。包括细胞增殖和存活，新陈代谢，分化和干性。对暴露于mTOR抑制剂引发的信号转导通路重新了解的详细知识，对于我们了解此类扰动在肿瘤中造成的后果（包括耐药细胞的出现）至关重要。