Yoon Sang-Oh, Shin Sejeong, Karreth Florian A, Buel Gwen R, Jedrychowski Mark P, Plas David R, Dedhar Shoukat, Gygi Steven P, Roux Philippe P, Dephoure Noah, Blenis John
Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
Mol Cell. 2017 Aug 3;67(3):512-527.e4. doi: 10.1016/j.molcel.2017.06.033. Epub 2017 Jul 27.
Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.
雷帕霉素哺乳动物靶蛋白（mTOR）的异常信号传导促成了癌细胞的毁灭性特征。因此，mTOR是一个关键的治疗靶点，其催化抑制剂正作为抗癌药物进行研究。尽管mTOR抑制剂最初会阻断细胞增殖，但某些癌细胞中的细胞活力和迁移能力会迅速恢复。尽管mTORC1/2信号传导受到持续抑制，但一种调节细胞存活和迁移的激酶Akt在其调节位点恢复了磷酸化。从机制上讲，mTORC1/2抑制促进整合素/粘着斑激酶介导的粘附体的重组，诱导IGFR/IR依赖性PI3K激活，并通过整合素/FAK/IGFR依赖性过程使Akt磷酸化。这种耐药机制促进了异种移植肿瘤细胞的生长，而mTOR加IGFR抑制剂可阻止这种生长，支持将这种联合用药作为癌症的一种治疗方法。
