PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展

目的:总结PI3K/Akt/mTOR信号通路靶向治疗在乳腺癌中的研究进展.方法:以“PI3K/Akt/mTOR、信号通路和乳腺癌”等为关键词,检索2000-01-2011-06 PubMed、Ovid和Springer等数据库的相关文献.纳入标准:1)关于PI3K/Akt/mTOR信号通路的组成、功能特点;2)PI3K/Akt/mTOR信号通路与乳腺癌的关系研究;3)以PI3K/Akt/mTOR信号通路中关键分子为靶点的乳腺癌治疗.根据纳入标准,符合分析的文献40篇.结果:信号转导通路的异常是肿瘤发生、发展的重要步骤,PI3K/Akt/mTOR信号通路与人类多种肿瘤密切相关,其在肿瘤细胞的增殖、存活、抵抗凋亡、血管发生和转移以及对放化疗抵抗中发挥了重要作用.乳腺癌中常见PI3K/Akt/mTOR信号通路的异常激活,以此通路为靶点的药物已成为乳腺癌治疗的研究热点.结论:靶向PI3K/Akt/mTOR通路中关键分子的众多药物在乳腺癌开展了一系列相关的临床试验研究,一部分显示出较好的安全性和有效性.随着对PI3K/Akt/mTOR通路的分子生物学机制的深入研究,期待靶向此通路的抑制剂将会在乳腺癌治疗中发挥巨大的作用,进一步提高乳腺癌患者的疗效和改善预后.     

PI3K/Akt信号通路在肿瘤化疗耐药中的作用

磷脂酰肌醇3-激酶-蛋白激酶B(PI3K/Akt)信号通路在细胞内发挥重要的作用,参与了许多生理和病理活动.目前研究发现在许多肿瘤中过度激活的PI3K/Akt信号通路与肿瘤化疗耐药的产生密切相关,体外研究显示采用PI3K/Akt信号通路抑制剂可以逆转肿瘤细胞的耐药.本文简要介绍了PI3K/Akt信号通路的基本组成结构,并重点介绍其在肿瘤化疗耐药中的作用.     

PI3K/AKT/mTOR信号通路介导乳腺癌内分泌治疗耐药的研究进展

内分泌治疗在激素受体阳性乳腺癌患者中的地位越来越受到重视,可以明显改善患者预后.内分泌治疗耐药严重制约着其临床应用,但耐药机制仍不明确,目前认为多信号通路激活参与耐药形成,其中PI3K/AKT/mTOR信号通路在耐药机制中发挥重要作用.临床试验提示,在内分泌治疗的基础上阻断信号通路可以逆转耐药,研究结果令人鼓舞.本文对PI3K/AKT/mTOR信号通路在内分泌耐药机制中的作用进行综述.     

PI3K/Akt信号通路与肿瘤血管新生的研究进展

PI3K/Akt信号通路在多种细胞中活化,参与细胞的增殖、分化、凋亡、血管新生等病理、生理过程。血管的生成需要PI3K/Akt信号通路的激活,PI3K/Akt活化后可以广泛诱导鸡胚尿囊膜血管的生成。PI3K/Akt信号通路与其下游信号分子mTOR及多种促血管新生因子,如VEGF、HIF等相互作用,从而促进肿瘤血管新生。PI3K/Akt信号通路抑制剂能够抑制其血管新生作用,因此靶向PI3K/Akt信号通路为恶性肿瘤靶向治疗提供了新方法。     

PI3K抑制剂与非小细胞性肺癌

磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase,PI3K)/蛋白激酶B(protein kinase B,Akt)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路是人体中的重要信号通路,通过逐级磷酸化下游蛋白发挥作用.非小细胞肺癌(non-small cell lung cancer,NSCLC)中存在该信号通路的异常活化.活化的信号通路可以改变NSCLC细胞的增殖、凋亡、侵袭和迁移等生物学特性从而影响其对治疗药物的反应及预后.针对该通路抑制剂的研究很多,部分抑制剂已进入临床研究阶段.PI3K抑制剂包括广谱PI3K抑制剂、亚型特异性的PI3K抑制剂和PI3 K/mTOR双重抑制剂.PI3K抑制剂单药有效率较低,但与化疗药物或其他靶向药物联用取得了不错的临床效果,目前往往将P IK3 CA突变以及抑癌基因PTEN的缺失作为预测疗效的指标,但准确性欠佳,进一步筛选疗效预测指标是目前面临的重要问题.     

PI3K/Akt/mTOR信号通路抑制剂在尤文肉瘤治疗中的研究进展

磷脂酰肌醇-3激酶(PI3K)/蛋白激酶B(PKB,又称Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路与细胞的生长、增殖、分化、凋亡、代谢等密切相关,研究发现在包括尤文肉瘤在内的多种实体肿瘤中存在该信号通路的异常.近年来,以PI3K/Akt/mTOR抑制剂来抑制该通路特定位点的靶向治疗已成为抗肿瘤的研究热点.而尤文肉瘤作为一个高度侵袭性、低分化的骨与软组织的恶性肿瘤,针对PI3K/Akt/mTOR信号通路的分子靶向治疗对于提高患者的生存预后具有重要意义.     

PI3K/AKT信号通路轴在肿瘤上皮细胞间质转化中作用的研究进展

肿瘤上皮间质转化（epithelial-mesenchymal transition,EMT）与肿瘤耐药、侵袭、迁移、发生远处转移等生物学行为密切相关.肿瘤微环境中多种细胞因子及其激活的信号通路均参与细胞的EMT.近年来,越来越多的文献报道PI3K/AKT信号转导途径在肿瘤细胞发生EMT过程中的作用尤为重要.本文将重点讨论PI3K/AKT途径在对E-钙黏蛋白（E-cadherin,E-Cad）的调控及其与其他信号通路协同诱发EMT过程中的作用,并对PI3 K/AKT抑制剂在肿瘤治疗的研究进行回顾.     

三阴性乳腺癌中PI3K/AKT/mTOR信号通路的突变及相关靶向治疗的研究进展

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型,PI3K/AKT/mTOR信号通路失调是TNBC最常见的致癌突变之一,靶向PI3K/AKT/mTOR信号通路是治疗TNBC的重要方向。本文着重介绍了PI3K/AKT/mTOR信号通路的机制,TNBC中出现的PIK3CA、AKT1或mTOR的突变,以及失活张力PTEN、PIK3R1或INPP4B的突变或丢失,也展现了布帕尼西、帕他色替、依维莫司等PI3K/AKT/mTOR信号通路靶向药物在治疗TNBC中单独、联合应用和与化疗或免疫疗法联用的疗效,同时论述了目前正在进行的各类临床试验及其未来的前景。     

VES对MDA-MB-453细胞PI3K/Akt信号通路的影响

目的：检测维生素E琥珀酸酯（vitamin E succinate,VES）对MDA-MB-453乳腺癌细胞PI3K/Akt信号通路中PI3K及Akt表达的影响。方法：不同浓度VES作用于人乳腺癌细胞MDA-MB-453（Her-2过表达株）24h和48h,VES的浓度分别为5、10和20μg/ml。RT-PCR法检测VES作用前后PI3K及Akt的mR-NA表达变化。结果：VES对MDA-MB-453乳腺癌细胞PI3 K/Akt信号通路中PI3 K有抑制作用（P〈0.05）,并呈时间-剂量依赖关系;而对Akt无明显的抑制作用（P〉0.05）。结论：VES可能是通过作用于PI3K/Akt信号通路而发挥其对MDA-MB-453乳腺癌细胞的抑制及凋亡作用。     

PI3K/AKT通路在肺癌转移和耐药中的研究

磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(phosphatidyl-inositol 3-kinase/serine-threonine kinase,PI3K/AKT)信号通路是细胞内重要信号转导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥抑制凋亡、促进增殖的关键作用,与人类多种肿瘤的发生发展密切相关。研究表明PI3K/AKT信号通路在恶性肿瘤细胞的增殖、血管新生和转移及对放化疗的拮抗中都起着重要作用。对PI3K/AKT信号通路的深入研究有望找到肿瘤预防和药物治疗的新靶点。本文简要介绍了PI3K/AKT信号通路的组成与功能调节,并着重阐述了其在肺癌转移和耐药中的作用。     

mTOR抑制剂在乳腺癌内分泌治疗耐药中的研究进展

PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。      

P13K／AKT／mTOR信号通路在乳腺癌Her-2治疗耐药中的作用研究进展

Her-2靶向治疗是Her-2过表达乳腺癌治疗的重要组成部分,但Her-2靶向治疗的耐药严重影响了乳腺癌的治疗。研究证实乳腺癌Her-2靶向治疗出现耐药的过程中有P13K／AKT／mTOR信号通路的激活,因此对P13K／AKT／mTOR信号通路及以P13K／AKT／mTOR信号通路为靶点的药物研究对乳腺癌治疗具有重要意义。     

The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer

Epidemiologic and experimental studies support a key role of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the biology of human cancers. Alterations resulting in activation of PI3K/Akt/mTOR signaling are perhaps the most frequent events observed in solid tumors, including breast cancer, and contribute to neoplastic transformation. The PI3K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of phosphatase and tensin homolog (PTEN) expression, or by mutations in growth factor receptors Ras, PTEN, or PI3K itself. Activation of this pathway contributes to cell cycle proliferation, growth, cell cycle entry, survival, cell motility, protein synthesis, and glucose metabolism, all important aspects of tumorigenesis. The most common genetic aberrations in breast cancer are activating somatic missense mutations in the gene encoding the p110a (PIK3CA) subunit of PI3K. The PTEN gene is often hypermethylated or decreased in expression, through as yet unclear mechanisms, in breast cancer. Studies have shown that PI3K/PTEN/AKT pathway modulation is implicated in HER2/neu-tumorigenesis and in response to the HER2-targeting antibody trastuzumab. Components of the pathway are regulated by feed-back and cross-talk to other signaling cascades and appear to be implicated with drug resistance. Over the past few years, a number of components of this signaling cascade have been the subject of intense drug-discovery activities. Rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. Newer-generation PI3K, AKT, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. This article summarizes the progress made in the elucidation of the pathway, clinical implications in pathology of breast cancer, and reviews novel drugs targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mTOR, currently undergoing clinical trials. Potential combination strategies, safety concerns, and resistance mechanisms for this new generation of anticancer agents are also discussed.     

Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway.

The PTEN protein is a lipid phosphatase with putative tumor suppressing abilities, including inhibition of the PI3K/Akt signaling pathway. Inactivating mutations or deletions of the PTEN gene, which result in hyper-activation of the PI3K/Akt signaling pathway, are increasingly being reported in human malignancies, including breast cancer, and have been related to features of poor prognosis and resistance to chemotherapy and hormone therapy. Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the PI3K/Akt signaling pathway becomes a fundamental proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore further this hypothesis in breast cancer cells. To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels. The PTEN-negative cell line displayed greater sensitivity to the growth inhibitory effects of the PI3K inhibitor, LY294002 and rapamycin, an inhibitor of the PI3K/Akt downstream mediator mTOR, compared with the PTEN-positive cell lines. To determine whether or not these differences in response are specifically due to effects of PTEN, we developed a series of cell lines with reduced PTEN protein expression compared with the parental cell line. These reduced PTEN cells demonstrated an increased sensitivity to the anti-proliferative effects induced by LY294002 and rapamycin compared with the parental cells, which corresponded to alterations in cell cycle response. These findings indicate that inhibitors of mTOR, some of which are already in clinical development (CCI-779, an ester of rapamycin), have the potential to be effective in the treatment of breast cancer patients with PTEN-negative tumors and should be evaluated in this setting.     

A novel imidazopyridine derivative,HS-106, induces apoptosis of breast cancer cells and represses angiogenesis by targeting the PI3K/mTOR pathway

Abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is an essential step for the formation and growth of tumors in humans. HS-106 is an imidazopyridine derivative that inhibits the kinase activity of PI3K by binding to the ATP-binding cleft. We found that this compound suppressed breast cancer cell proliferation and induced apoptosis by specifically inhibiting the activity of target proteins in the PI3K/Akt/mTOR signaling pathway. Cell cycle analysis revealed that treatment with HS-106 resulted in cell cycle arrest at the G₂/M phase due to up-regulation of p-cdc25 and down-regulation of cyclin B1. Also, HS-106 induced apoptosis by increasing the levels of cleaved caspase-3 and cleaved PARP. In addition, chromatin condensation and apoptotic bodies were detected in HS-106-treated breast cancer cells. Furthermore, HS-106 decreased the expression of hypoxia-inducible factor 1α (HIF-1α), and inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs) in vitro and blood vessel formation in an in vivo Matrigel plug assay. These results show that HS-106 may be an effective novel therapeutic candidate in clinical trials as a potential treatment for human breast cancers or other advanced malignancies with aberrant PI3K/Akt/mTOR signaling.     

Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.     

Inhibition of constitutively activated phosphoinositide 3‐kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1‐defective breast cancer cells

Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1‐defective human breast cancer cells. Levels of phospho‐AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho‐AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de‐sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI‐103, and BEZ235, showed anti‐proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti‐proliferative effects of gemcitabine by enhancing caspase‐3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1‐defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers. © 2012 Wiley Periodicals, Inc.     

NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha.