PI3K-Akt-mTOR信号传导通路与乳腺癌关系的研究进展

PI3K-Akt-mTOR信号传导通路在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该通路涉及多基因,当原癌基因活化或抑癌基因失活时均可导致通路异常激活进而引发肿瘤的形成,研究表明乳腺癌中该通路常异常激活。针对不同亚型乳腺癌,该通路及相关基因的表达水平存在差异。本文将对PI3K-Akt-mTOR信号传导通路的异常激活机制及其与所涉及的关键基因在不同亚型乳腺癌中的表达水平及作用机制加以综述,以期为不同亚型乳腺癌的诊断、治疗和预后判断提供参考。     

PI3K/Akt/mTOR信号通路抑制剂在乳腺癌治疗中的应用研究

目的 研究PI3K/Akt/mTOR信号通路抑制剂在乳腺癌治疗中的应用.方法 应用ADP-GloTMLipidKinaseSystems对PO系列化合物在PI3Kα激酶水平的抑制活性进行初步筛选,对待测化合物100nM进行五倍的梯度稀释,计算IC50.P13K激酶各亚型IC50测定操作进行筛选,基于酶浓度的不同,对mTOR激酶的水平进行测定.借助大鼠试验测定PO-23化合物体内外抗乳腺癌的活性.为了探讨PO-23化合物的抗肿瘤作用机制对细胞进行培养,检测细胞的凋亡和自噬.结果 研究结果表明,筛选出乳腺癌的选择性较强,PI3K-mTOR抑制剂的抑制性能较好.在实验研究中所筛选出来的PI3K-mTOR双靶点抑制剂在乳腺癌细胞FASN当中过表达.在细胞的抑制和自噬当中,PI3K/Akt/mTOR可以抑制MDA-MB-231的细胞增殖,有着浓度和时间的依赖性.相较于空白对照组,PI3K/Akt/mTOR的细胞凋亡率明显较高,且在数据的对比中具有统计学差异(P＜0.05).结论 PI3K/Akt/mTOR信号通路抑制剂在乳腺癌的治疗中有较高的应用价值,可以抑制PI3K/Akt/mTOR信号通路磷酸化,抑制细胞的增殖,对乳腺癌治疗有治疗的作用,值得临床推广并且应用.     

PI3K/Akt/mTOR信号转导通路与淋巴瘤形成

大量研究显示PI3K/Akt/mTOR信号通路的异常激活在淋巴瘤的形成及发展中起着重要作用,该信号通路上主要分子的抑制剂为淋巴瘤的靶向治疗提供了新方向.本综述介绍并总结了PI3K/Akt/mTOR信号传导通路概况、该通路在各淋巴瘤亚型上的最新研究发现以及mTOR抑制剂在淋巴瘤靶向治疗方面的应用前景.     

磷脂酰肌醇-3激酶抑制剂在复发/难治性滤泡淋巴瘤研究中的新进展

磷脂酰肌醇-3激酶(PI3K)信号通路的过度激活与包括滤泡淋巴瘤(FL)在内的多种血液系统恶性肿瘤的发生、发展密切相关。PI3K通过激活下游多个信号通路靶点,参与调节细胞生长、增殖、分化、迁移及凋亡。PI3K抑制剂通过抑制PI3K,阻断PI3K/AKT/mTOR信号通路,抑制血液系统恶性肿瘤的发生、发展。近年来,PI3...     

乳腺癌细胞ret基因转录水平的表达及其与PI3KAktmTOR信号通路相关因子的关系

目的探讨乳腺癌细胞ret基因转录水平的表达及其与PI3KAktmTOR信号通路相关因子的关系。方法以乳腺癌细胞为研究对象,采用荧光定量聚合酶链式反应(RT-PCR)检测细胞中RET、PI3K、mTOR和AKT mRNA表达量,构建合成ret shRNA慢病毒载体,转染乳腺癌细胞,再次采用RT-PCR检测细胞中RET、PI3K、mTOR和AKT mRNA表达量。比较转染前后细胞中RET、PI3K、mTOR和AKT mRNA表达量,并采用Pearson线性相关分析法分析其细胞中RET mRNA表达量与其PI3K、mTOR和AKT mRNA表达量的关系。结果转染前细胞中RET、PI3K、mTOR和AKT mRNA表达量分别为0.851±0.126、0.872±0.126、0.845±0.087和0.769±0.355,均分别高于转染后的0.108±0.023、0.113±0.022、0.098±0.022和0.072±0.013(P<0.05)。Pearson线性相关分析结果显示,细胞中RET mRNA表达量与其PI3K、mTOR和AKT mRNA表达量均呈正相关(r=0.877、0.852、0.863,P<0.05)。结论乳腺癌细胞ret基因转录水平较高且与PI3KAktmTOR信号通路相关因子密切相关,可能通过调控PI3KAktmTOR信号通路而影响乳腺癌的发生发展,可能作为乳腺癌治疗的靶基因之一。     

PI3K-Akt-mTOR信号转导通路与病理性疼痛的研究进展

PI3K-Akt-mTOR信号转导通路是生物体内重要的信号转导系统之一,在多种生理功能的调节中发挥着重要作用。近年来研究表明,PI3K-Akt-mTOR信号转导通路还参与了病理性疼痛的发生、发展过程,其激活后能够诱导和维持不同条件下的痛敏反应。随着对这一信号通路研究的深入,不仅能够在细胞、分子水平对病理性疼痛机制进行更深入的探讨,而且能够为病理性疼痛的临床治疗提供新的靶点。     

IGF-1/PI3K/Akt/mTOR信号通路失衡与孤独症关系研究进展

IGF-1/PI3K/Akt/mTOR信号通路在调节细胞生长、增殖、分化、能动性、生存、代谢和蛋白质合成过程中起重要作用。孤独症是广泛性发育障碍疾病,病因机制复杂,其发展与其分子机制改变是近年研究的热点。IGF-1/PI3K/Akt/mTOR信号通路失调与孤独症发生有关,该信号通路在孤独症的诊断、治疗中可能有重要作用。本文就IGF-1/PI3K/Akt/mTOR信号通路失衡与孤独症关系的研究进展作一综述。     

PI3K／AKT／mTOR信号通路在造血干细胞中作用的研究进展

PI3K／AKT／mTOR信号通路调节细胞生长、增殖和存活等生命过程,在多种细胞生命过程中起着关键的作用,在造血干细胞中同样也扮演着重要的角色。过度激活PI3K／AKT／mTOR信号通路会造成造血干细胞的耗竭,而抑制PI3K／AKT／mTOR信号通路,则B细胞的分化会受到显著的抑制。本文系统介绍PI3K／AKT／mTOR信号通路中关键节点的蛋白,包括PI3K,AKT,mTOR,FoxO和GSK-3等在造血干细胞中作用的最新研究进展。     

mTOR抑制剂在去势抵抗性前列腺癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)是磷脂酰肌醇-3羟基激酶/蛋白激酶B/mTOR(PI3K/Akt/mTOR)信号通路中的关键蛋白,与肿瘤细胞的发生发展存在密切联系,参与肿瘤细胞的侵袭与转移。在去势抵抗性前列腺癌(castration resistant prostate cancer,CRPC)中,约有50%的病例的PI3K/Akt/mTOR信号通路过度激活,且PI3K/Akt/mTOR信号通路的异常活化通常是诱导前列腺癌向CRPC进展的原因。这表明靶向针对该途径的治疗方法可能在提高患者生存率方面具备显著疗效。本文以期通过总结CRPC中PI3K/Akt/mTOR通路的生物学特点、功能、治疗及联合用药,为CRPC寻找新的分子治疗靶点提供参考。     

柔红霉素联合雷帕霉素对急性白血病原代细胞增殖作用的影响

雷帕霉素(Rapamycin,RPM)是一类从吸水性链霉菌中分离的大环内酯类抗生素,是哺乳动物雷帕霉素靶蛋白(mTOR)的特异性抑制剂,因其强效的免疫抑制和抗细胞增殖活性已广泛用于器官移植后急性排异反应的防治[1].近年研究发现,PI3K/AKT/mTOR信号通路活化能加速细胞周期过程、减少细胞凋亡、促进肿瘤细胞迁移,与多种肿瘤发生密切相关[2-3].血液系统的恶性肿瘤,尤其是白血病也存在mTOR及其相关信号通路的异常激活[1,4].     

Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor–positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.     

Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be activated by radiation. The mammalian target of rapamycin (mTOR) is downstream of Akt, and we investigated the effects of radiation on Akt/mTOR signaling in breast cancer cell models. RAD001 (everolimus), a potent derivative of the mTOR inhibitor rapamycin, was used to study the effects of mTOR inhibition, as the role of mTOR inhibition in enhancing radiation remains unexplored. RAD001 decreased clonogenic cell survival in both breast cancer cell lines MDA-MB-231 and MCF-7, although the effect is greater in MDA-MB-231 cells. Irradiation induced Akt and mTOR signaling, and this signaling is attenuated by RAD001. The radiation-induced signaling activation is mediated by PI3K because inhibition of PI3K with LY294002 inhibited the increase in downstream mTOR signaling. Additionally, caspase-dependent apoptosis is an important mechanism of cell death when RAD001 is combined with 3 Gy radiation, as shown by induction of caspase-3 cleavage. An increase in G(2)-M cell cycle arrest was seen in the combination treatment group when compared with controls, suggesting that cell cycle arrest may have been a contributing factor in the increased radiosensitization seen in this study. We conclude that RAD001 attenuates radiation-induced prosurvival Akt/mTOR signaling and enhances the cytotoxic effects of radiation in breast cancer cell models, showing promise as a method of radiosensitization of breast cancer.     

Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

The receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) pathway is frequently altered in cancer, but the underlying mechanism leading to tumorigenesis by activated mTOR remains less clear. Here we show that mTOR is a positive regulator of Notch signaling in mouse and human cells, acting through induction of the STAT3/p63/Jagged signaling cascade. Furthermore, in response to differential cues from mTOR, we found that Notch served as a molecular switch to shift the balance between cell proliferation and differentiation. We determined that hyperactive mTOR signaling impaired cell differentiation of murine embryonic fibroblasts via potentiation of Notch signaling. Elevated mTOR signaling strongly correlated with enhanced Notch signaling in poorly differentiated but not in well-differentiated human breast cancers. Both human lung lymphangioleiomyomatosis (LAM) and mouse kidney tumors with hyperactive mTOR due to tumor suppressor TSC1 or TSC2 deficiency exhibited enhanced STAT3/p63/Notch signaling. Furthermore, tumorigenic potential of cells with uncontrolled mTOR signaling was suppressed by Notch inhibition. Our data therefore suggest that perturbation of cell differentiation by augmented Notch signaling might be responsible for the underdifferentiated phenotype displayed by certain tumors with an aberrantly activated RTK/PI3K/AKT/mTOR pathway. Additionally, the STAT3/p63/Notch axis may be a useful target for the treatment of cancers exhibiting hyperactive mTOR signaling.     

CSCO乳腺癌HR阳性晚期乳腺癌内分泌治疗的进展

随着有关CDK4/6抑制剂、HDAC抑制剂、PI3K/Akt/mTOR抑制剂临床研究的不断深入,激素受体阳性晚期乳腺癌的内分泌治疗进入了靶向联合时代。面对诸多新型药物,如何制定最优化和个体化的治疗方案成为广大临床医生关注的焦点。2020年新版CSCO乳腺癌指南充分考量循证医学证据等级、治疗手段可及性及最新研究进展,并针对既往用药情况提出分层策略,对激素受体阳性晚期乳腺癌的内分泌治疗方案予以相应推荐,为广大乳腺癌医学工作者在临床实践中作出合理选择提供了指导依据。     

Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.     

Cotargeting survival signaling pathways in cancer

Mammalian target of rapamycin (mTOR) is a component of a signaling pathway (PTEN/PI3K/AKT) that is frequently dysregulated in cancer. However, its precise relationship to the MAPK cascade (Ras/Raf/MEK/ERK), another pathway often implicated in tumorigenesis, has not been well defined. Recent evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption. In this issue of the JCI, Waugh Kinkade et al. and Carracedo et al. examine the relationship between these pathways in prostate and breast cancer cell model systems (see the related articles beginning on pages 3051 and 3065, respectively). Their findings suggest a link between inhibition of mTOR and ERK activation, possibly reflecting interruption of a novel negative S6K1-dependent feedback loop. Significantly, both groups observed that simultaneous inhibition of MEK/ERK and mTOR resulted in substantially enhanced antitumor effects both in vitro and in vivo. Together, these findings suggest that concurrent interruption of complementary signaling pathways warrants further investigation in cancer therapy.     

ErbB family receptor inhibitors as therapeutic agents in breast cancer: current status and future clinical perspective

Breast cancer is the most common cancer diagnosed in women and the second most common cause of female cancer-related deaths, with more than one million new cases diagnosed per year throughout the world. With the recent advances in the knowledge of cellular processes and signaling pathways involved in the pathogenesis of breast cancer, the current focus of researchers and clinicians is to develop novel treatment strategies that can be included in the armamentarium against breast cancer. With the failure of endocrine-targeted therapy and the development of resistance to existing chemotherapy, the most explored pathway as next generation target for breast cancer therapy has been the epidermal growth factor receptor (EGFR) (ErbB-1)/herceptin-2 (HER-2) (ErbB-2) pathway. This review focuses on the rationale for targeting members of ErbB receptor family and numerous agents that are in use for inhibiting the pathway. The mechanism of action, preclinical and clinical trial data of the agents that are in use for targeting the EGFR/HER-2 pathway and the current status, thereof, have been discussed in detail. In addition, the future clinical trial promises these agents hold either as monotherapy or as combination therapy with conventional agents or with other antisignaling agents have been pondered, so as to provide better and more efficacious treatment strategies for breast cancer patients.     

GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic.     

New-Onset Heart Failure in Association With Severe Hypertension During Trastuzumab Therapy

Heart failure is a dreaded complication of trastuzumab therapy in women with breast cancer overexpressing the human epidermal growth factor receptor (HER)-2. Experimental studies have pointed out that the HER-2 signaling pathway is important in the adaptation to high afterload conditions and its inactivation leads to cardiac decompensation. Herein, we report on 2 patients with breast cancer who were receiving trastuzumab monotherapy and required hospital admission for new-onset heart failure. This occurred at a time of unprecedented blood pressure elevations, in one case due to cessation of antihypertensive medications and in the other case due to a scleroderma crisis. Although trastuzumab may not have been the precipitating factor for blood pressure dyscontrol in these patients, severe, uncontrolled hypertension may have been the precipitating factor for trastuzumab-related acute heart failure. These 2 cases add to previous reports recognizing systemic hypertension as a risk factor for the development of trastuzumab cardiotoxicity and translate experimental observations of the significance of the HER-2 signaling pathway to the bedside. Pending further confirmation, the present observations may raise awareness of the need for appropriate monitoring and control of systemic hypertension in patients receiving trastuzumab, or potentially any other HER-2–targeted therapy.