Current development of the second generation of mTOR inhibitors as anticancer agents

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a "master switch" for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.

PI3K/Akt/mTOR信号通路及临床相关肿瘤抑制剂

哺乳动物雷帕霉素靶(mTOR)和蛋白激酶B(Akt/PKB)与肿瘤发生的密切关系已被广泛地认可.mTOR是一种丝/苏氨酸激酶,可以通过影响mRNA转录、代谢、自噬等方式调控细胞的生长.它既是PI3K的效应分子,也可以是PI3K的反馈调控因子.mTORC1和mTORC2是mTOR的两种不同复合物.对雷帕霉素敏感的mTORC1受到营养、生长因子、能量和应激4种因素的影响.生长因子通过PI3K/Akt信号通路调控mTORC1是最具特征性调节路径.而mTORC2最为人熟知的是作为Akt473磷酸化位点的上游激酶.同样,Akt/PKB在细胞增殖分化、迁移生长过程中发挥着重要作用.随着Thr308和Ser473两个位点激活,Akt/PKB也得以全面活化.因此,mTORC2-AktmTORC1的信号通路在肿瘤形成和生长中是可以存在的.目前临床肿瘤治疗中,PI3K/Akt/mTOR是重要的靶向治疗信号通路.然而,仅抑制mTORC1活性,不是所有的肿瘤都能得到预期控制.雷帕霉素虽然能抑制mTORC1,但也能反馈性地增加PI3K信号活跃度,从而影响治疗预后.近来发现的第二代抑制剂可以同时抑制mTORC1/2和PI3K活性,这种抑制剂被认为在肿瘤治疗上颇具前景.本综述着重阐述了PI3K/Akt/mTOR信号通路的传导、各因子之间的相互调控以及相关抑制剂的发展.

Inhibition of mammalian target of rapamycin induces phenotypic reversion in three-dimensional cultures of malignant breast epithelial cells

Inhibition of mammalian target of rapamycin (m- TOR) is a potential method for cancer treatment. Effects of rapamycin (RAP) on the reversion of malignant breast epithelial cells were investigated on three-dimensional (3D) basement membrane extract (BME) cultures. Through continuous exposure to 20 nM of RAP, cell colony size was significantly reduced in 3D BME cultures of malignant breast epithelial cells, while normal cell colony size appeared unaffected. In unfixed 3D BME cultures of normal and RAP-treated malignant breast epithelial cells, the presence of luminal cell death was confirmed by ethidium bromide and propidium iodide labeling. Increased structural organization was observed by im- munofluorescence staining of F-actin and β-catenin in RAP-treated malignant breast epithelial cells. In monolayer cultures of normal and malignant breast epithelial cells, continuous exposure to 20 nM of RAP increased caspase 3/7 activity and decreased proliferation. Reverse transcriptase polymerase ch- ain reaction (RT-PCR) array analysis indicated a fold increase in the expression of a number of proteins related to polarity, cell-cell adhesion, and cell-matrix adhesion in the presence of RAP. Our data showed that phenotypic reversion of malignancy can be ach- ieved through RAP exposure on 3D BME cultures. This 3D BME culture system will provide correct microenvironments for observing the effects of other mTOR inhibitors on phenotypic reversion of malignant breast epithelial cells.

乳腺癌中PI3K通路生物标记物的临床疗效预测

乳腺癌中常有PI3K/Akt/mTOR信号通路的异常,现有的证据提示,PI3K/Akt/mTOR是促进细胞增殖、代谢、存活、转移以及抗肿瘤治疗耐药等功能的重要信号通路之一,该通路中的生物标记物可能预测联合雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)抑制剂的乳腺癌治疗的临床疗效,本文就此作一回顾性论述。

依维莫司引起的非感染性肺炎1例病例报道及文献复习

依维莫司作为一种口服的雷帕霉素靶蛋白抑制剂,可用于激素受体阳性的进展期乳腺癌治疗。非感染性肺炎(NIP)是依维莫司治疗相关的重要不良反应。尽管依维莫司所致NIP通常症状较轻并可控,但是其却是导致依维莫司剂量调整及停药的主要不良反应,甚至可能导致死亡。因此,依维莫司导致的NIP需要及时诊断和治疗。本文报道1例阿那曲唑辅助内分泌治疗9个月后胸壁复发的乳腺癌病例,该患者在服用依维莫司联合依西美坦3个月后出现NIP。该患者的胸部CT表现为两肺内散在斑片影,并出现咳嗽以及轻度呼吸困难。依维莫司减量50%处理后1周,患者的相关症状明显好转。本文对相关文献进行了复习,并对乳腺癌患者中依维莫司所致NIP的诊断、发生率、发生机制及处理原则进行了讨论。