Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway plays a critical role in many cellular functions which are elicited by extracellular stimuli. However, constitutively active PI3K/Akt/mTOR signaling has also been firmly established as a major determinant for cell growth, proliferation, and survival in an wide array of human cancers. Thus, blocking the PI3K/AKT/mTOR signal transduction network could be an effective new strategy for targeted anticancer therapy. Pharmacological inhibitors of this signaling cascade are powerful antineoplastic agents in vitro and in xenografted models of tumors, and some of them are now being tested in clinical trials. Recent studies showed that PI3K/Akt/mTOR axis is frequently activated in acute myelogenous leukemia (AML) patient blasts and strongly contributes to proliferation, survival, and drug-resistance of these cells. Both the disease-free survival and overall survival are significantly shorter in AML cases with PI3K/Akt/mTOR upregulation. Therefore, this signal transduction cascade may represent a target for innovative therapeutic treatments of AML patients. In this review, we discuss the possible mechanisms of activation of this pathway in AML cells and the downstream molecular targets of the PI3K/Akt/mTOR signaling network which are important for blocking apoptosis, enhancing proliferation, and promoting drug-resistance of leukemic cells. We also highlight several pharmacological inhibitors which have been used to block this pathway for targeted therapy of AML. These small molecules induce apoptosis or sensitize AML cells to existing drugs, and might be used in the future for improving the outcome of this hematological disorder.     

Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML.

Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival. Although abnormalities of mTOR signaling are strongly associated with neoplastic leukemic proliferation, the role of pharmacologic inhibitors of mTOR in the treatment of AML has not been established.

Expert opinion: Inhibition of mTOR signaling has in general modest growth-inhibitory effects in preclinical AML models and clinical trials. Yet, combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy. In turn, dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity in pre-clinical AML models. Further, understanding the role of mTOR signaling in stemness of leukemias is important because AML stem cells may become chemoresistant by displaying aberrant signaling molecules, modifying epigenetic mechanisms, and altering the components of the bone marrow microenvironment.     

New inhibitors of the mammalian target of rapamycin signaling pathway for cancer

Importance of the field: Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types.

Areas covered in this review: The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules.

What the reader will gain: New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway.

Take home message: Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.     

Akt as a therapeutic target in cancer

Background: The phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/v-akt murine thymoma viral oncogene homolog (Akt)/mammalian target of rapamycin (mTOR) pathway is central in the transmission of growth regulatory signals originating from cell surface receptors. Objective: This review discusses how mutations occur that result in elevated expression the PI3K/PTEN/Akt/mTOR pathway and lead to malignant transformation, and how effective targeting of this pathway may result in suppression of abnormal growth of cancer cells. Methods: We searched the literature for articles which dealt with altered expression of this pathway in various cancers including: hematopoietic, melanoma, non-small cell lung, pancreatic, endometrial and ovarian, breast, prostate and hepatocellular. Results/conclusions: The PI3K/PTEN/Akt/mTOR pathway is frequently aberrantly regulated in various cancers and targeting this pathway with small molecule inhibitors and may result in novel, more effective anticancer therapies.     

The mTOR protein as a target in thyroid cancer

Introduction: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents.

Areas covered: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer.

Expert opinion: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

Endothelin (ET), its Precursor BigET,and its Receptor,ETA

Introduction: The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. The pathway is frequently active in many different types of cancer—e.g., breast, bladder, prostate, thyroid, ovarian and NSCLC. Targetable genetic aberrations in this pathway give us many opportunities for development of targeted therapies for different types of cancer.

Areas covered: The genetic alterations in the PI3K/mammalian target of rapamycin (mTOR)/Akt pathway, as well as the drugs that target this pathway, either alone, in combination with other targeted agents or in chemotherapy. Targeted inhibitors of the PI3K pathway currently being tested in clinical trials in different types of human cancer.

Expert opinion: Small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway show some success with these agents in current clinical trials. For further improvement in response, molecular correlates that can be used for patient selection, need to be determined. A more efficient and effective way to screen for patients to determine which patients are most likely to benefit from PI3K pathway inhibitors is also needed.     

The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19

Coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global health. The disregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) cell signaling pathway observed in patients with COVID-19 has attracted attention for the possible use of specific inhibitors of this pathway for the treatment of the disease. Here, we review emerging data on the involvement of the PI3K/Akt/mTOR pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical studies investigating its tailored inhibition in COVID-19. Current in silico, in vitro, and in vivo data convergently support a role for the PI3K/Akt/mTOR pathway in COVID-19 and suggest the use of specific inhibitors of this pathway that, by a combined mechanism entailing downregulation of excessive inflammatory reactions, cell protection, and antiviral effects, could ameliorate the course of COVID-19.     

Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review

Introduction: The mammalian target of rapamycin (mTOR) is a protein kinase and a key component of the PI3K/Akt/mTOR signaling pathway, and is deregulated in half of all human cancers. Rapamycin and its analogs (rapalogs) are allosteric inhibitors of one functional mTOR complex, mTORC1, and are clinically proven therapeutic agents for the treatment of certain cancers. However, rapalogs mainly partially inhibit mTORC1, while ATP competitive inhibitors suppress both mTORC1 and mTORC2, and therefore may offer advantages in the clinic. Recently, small-molecule inhibitors have entered clinical trials that are mTOR-selective or dual mTOR/PI3K inhibitors.

Areas covered: This review focuses on ATP-competitive mTOR inhibitors that have appeared in the patent literature in 2010. Many inhibitors with new structural motifs have been discovered as well as inhibitors that are related to previously disclosed structures. This review endeavors to put into perspective the diverse structural elements that make up these compounds. Patent applications are covered that include either selective mTOR inhibitors or dual mTOR/PI3K inhibitors.

Expert opinion: The PI3K/mTOR signaling pathway is an exciting target for the development of pharmaceuticals to treat cancer and other diseases, due to the unique combination of a clinically and commercially validated pathway approach (i.e., rapalogs), combined with a biological rationale for further increased efficacy (i.e., ATP-competitive inhibitors). With the number of candidate drugs currently in development or at earlier stages of the drug discovery pipeline, we are bound to see small-molecule inhibitors reach pivotal trials, and hopefully the market, in the near future.     

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells

Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.     

丹参酮IIA通过调控PI3K/Akt/mTOR信号通路对食管癌细胞放疗敏感性的影响

目的 研究丹参酮II_A对人食管癌细胞放疗敏感性的影响，并基于磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）信号通路探讨其潜在机制。方法 以人食管癌Eca-109细胞为受试细胞，分别采用不同浓度丹参酮II_A和不同放射剂量处理Eca-109细胞，48 h后MTT法检测细胞增殖活力，计算丹参酮II_A半数抑制浓度（IC₅₀）和放射的IC₅₀，分别作为后续实验丹参酮II_A浓度和放射剂量。取对数生长期Eca-109细胞，设对照组、丹参酮II_A组、放射组、丹参酮II_A＋放射组、丹参酮II_A＋放射＋PI3K抑制剂（LY294002）组。通过平板克隆实验、MTT法、流式细胞术、荧光质粒转染法检测细胞克隆形成能力、增殖活力、凋亡率和自噬状况，RT-PCR、Western blotting法检测细胞中PI3K/Akt/mTOR信号通路相关mRNA和蛋白表达。结果 丹参酮Ⅱ_A和放射对人食管癌Eca-109细胞增殖活力的抑制作用均呈现剂量相关性，丹参酮II_A IC₅₀为8.75 mmol/L，放射量IC₅₀为4.63 Gy。与对照组相比，丹参酮II_A组、放射组、丹参酮II_A＋放射组、丹参酮II_A＋放射＋LY294002组细胞克隆形成能力和增殖活力明显降低，凋亡率和自噬体数量明显升高（P＜0.05）；PI3K、Akt、mTOR mRNA和蛋白表达量明显降低（P＜0.05）；Bcl-2、Bax、cleaved Caspase-3、LC3-I、LC3-II蛋白表达量及Bax/Bcl-2、Cleaved Caspase-3/Caspase-3、LC3-II/LC3-I明显升高（P＜0.05）。与丹参酮II_A组或放射组相比，丹参酮II_A＋放射组和丹参酮II_A＋放射＋LY294002组对各检测指标的调控作用明显增强（P＜0.05）。与丹参酮II_A＋放射组相比，丹参酮II_A＋放射＋LY294002组对各指标的调控作用明显增强（P＜0.05）。结论 丹参酮II_A可能通过下调PI3K/Akt/mTOR信号通路，抑制细胞增殖并促进其凋亡与自噬，进而增强人食管癌细胞放疗敏感性。     

用于肿瘤治疗的PI3K/mTOR双重抑制剂的研究进展

磷脂酰肌醇3-激酶（PBK）是细胞内重要的信号转导分子,在细胞存活、增殖和分化过程中起重要调节作用。且是磷脂酰肌醇3-激酶／蛋白激酶B／雷帕霉素靶蛋白信号转导通路的关键节点蛋白,与细胞周期、血管形成、肿瘤发生和侵袭的关系密切,现已证实PBKs是潜力巨大的药物治疗靶点,针对该通路的抑制剂近年来成为研究热点,抗肿瘤治疗前景看好。     

The mTOR protein as a target in thyroid cancer

INTRODUCTION: The mammalian target of rapamycin (mTOR) protein is a downstream effector of the phosphatidilinositol-3 kinase (PI3K)/Akt pathway, which regulates not only cell proliferation and viability, but also iodide uptake in thyroid cells. Genetic alterations in the PI3K/Akt/mTOR pathway are common during thyroid cancer progression, and thus, these proteins are attractive targets for cancer therapy. So far, specific mTOR inhibitors, such as rapamycin analogs, have been developed and studied as anti-cancer agents. AREAS COVERED: This review discusses evidence that justifies the potential use of mTOR signaling pathway inhibitors as therapeutic agents for thyroid cancer. EXPERT OPINION: In the near future, mTOR-targeted drugs might represent a new approach for the therapy of thyroid cancer patients; rapamycin analogs have already been developed and are currently being clinically tested. Besides the antiproliferative action of mTOR inhibition, the stimulatory effect on thyroid iodide uptake can also be useful in the treatment of recurrent thyroid cancer. Therefore, if rapamycin analogs are able to increase iodide uptake in thyroid cancer, either alone or in combination with other agents, this will represent a new approach for the treatment of thyroid cancer, which may possibly improve the treatment of patients in which radioiodine therapy is not effective.     

雷公藤红素通过PI3K/AKT/mTOR信号通路对胃癌MFC细胞增殖和凋亡的影响

目的研究雷公藤红素对胃癌MFC细胞内PI3K/AKT/mTOR信号通路的影响及其对胃癌MFC细胞增殖的抑制和促凋亡作用机制。方法分别设置对照组和雷公藤红素低、中、高剂量(5、10、20 mmol/L)组,采用MTT法检测雷公藤红素对胃癌MFC细胞增殖的影响;采用流式细胞技术检测雷公藤红素对胃癌MFC细胞周期的影响及MFC细胞凋亡的情况;Western blotting检测雷公藤红素对胃癌MFC细胞内凋亡相关蛋白Bax、Bcl-2和PI3K、AKT和mTOR蛋白表达的影响;实时定量PCR检测雷公藤红素对胃癌MFC细胞内PI3K、AKT和mTORm RNA表达的影响。结果与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制胃癌MFC细胞的增殖(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著引起MFC细胞G2/M期阻滞(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著促进MFC细胞的凋亡(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内抗凋亡蛋白Bcl-2蛋白和PI3K、AKT、mTOR蛋白的表达(P0.05),显著促进MFC细胞内促凋亡蛋白Bax的表达(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内PI3K、AKT和mTORm RNA的表达(P0.05)。结论雷公藤红素能够抑制胃癌MFC细胞的增殖并促进胃癌MFC细胞凋亡,其作用机制可能是通过抑制胃癌MFC细胞内PI3K/AKT/mTOR信号通路中PI3K、AKT、mTOR等蛋白的表达而抑制胃癌MFC细胞的增殖,进而促进胃癌MFC细胞内促凋亡蛋白Bax的表达,同时抑制抗凋亡蛋白Bcl-2的表达,从而促进胃癌MFC细胞凋亡。     

FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML

An appealing therapeutic target in AML is constitutively activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. There are currently several FLT3 inhibitors that are undergoing clinical investigation. However, the discovery of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to circumvent drug resistance. Here, we provide an overview of FLT3 inhibitors under preclinical and clinical investigation, and we discuss mechanisms whereby AML cells develop resistance to FLT3 inhibitors, and the ways in which combination therapy could potentially be utilized to override drug resistance. We discuss how the cross-talk between major downstream signaling pathways, such as PI3K/PTEN/Akt/mTOR, RAS/Raf/MEK/ERK, and Jak/STAT, can be exploited for therapeutic purposes by targeting key signaling molecules with selective inhibitors, such as mTOR inhibitors, HSP90 inhibitors, or farnesyltransferase inhibitors, and identifying those agents with the ability to positively combine with inhibitors of FLT3, such as PKC412 and sunitinib. With the widespread onset of drug resistance associated with tyrosine kinase inhibitors, due to mechanisms involving development of point mutations or gene amplification of target proteins, the use of a multi-targeted therapeutic approach is of potential clinical benefit.     

mTOR inhibition in breast cancer: unraveling the complex mechanisms of mTOR signal transduction and its clinical implications in therapy

Introduction: The mammalian target of rapamycin (mTOR)/PI3K/Akt pathway is altered in breast cancer cells, as demonstrated by mutations in both the upstream and downstream regulators of mTOR, including phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss or Akt/PI3K activation, and potentially in the mTOR protein itself. This contributes to increased cell proliferation, as well as growth-factor independence and endocrine resistance. Thus, mTOR inhibition holds considerable promise as a rational therapeutic strategy in breast cancer.

Areas covered: This review describes how dysregulation of the mTOR pathway in breast cancer may contribute to breast cancer pathogenesis, as well as discussing preclinical and clinical data that support mTOR inhibitor therapy.

Expert opinion: Direct blockade of the mTOR pathway is a new and intriguing area in breast cancer therapy, with the potential to modulate growth-factor and estrogen-dependent and -independent pathways, that contribute to the pathogenesis and progression of breast tumors. mTOR inhibitors demonstrate significant biologic activity with manageable toxicities, in combination with hormonal therapy and chemotherapy, in both the neoadjuvant and metastatic breast cancer settings.     

PI3K/Akt/mTOR通路在炎症相关疾病中分子机制研究进展

炎症是一种机体应对感染、组织损伤或者细胞应激的反应,并且可以通过修复机制恢复组织功能。炎症发生时会引起多条信号通路的激活,包括核转录因子-κB（NF-κB）通路、Janus激酶/信号转导与转录激活子（JAK/STAT）通路、丝裂原活化蛋白激酶（MAPK）通路以及磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白（PI3K/Akt/mTOR）通路等。本文综述了近年来磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白通路在炎症相关疾病中的分子作用机制,为研发以磷脂酰肌醇-3-激酶/蛋白激酶B /雷帕霉素靶蛋白为靶点的药物提供理论依据。     

布鲁顿酪氨酸激酶靶向药物的研究进展

目的 探究青藤碱（sinomenine, SIN）逆转人乳腺癌MCF-7细胞他莫昔芬（tamoxifen, TAM）耐药及其相关机制。方法 通过短时间高浓度TAM刺激MCF-7细胞诱导耐药株,采用MTT法检测细胞耐药性的改变;进一步通过MTT法检测SIN和TAM对耐药株MCF-7/TAM的毒性作用,并采用CompuSyn软件分析两药联用的联合指数,评价联合效应;采用流式细胞术检测两药对MCF-7/TAM细胞凋亡和周期的影响;采用Western blot法检测MCF-7/TAM细胞内PI3K/AKT/mTOR信号通路相关蛋白表达情况,以及SIN干预后,MCF-7/TAM细胞内PI3K/AKT/mTOR信号通路相关蛋白的表达情况。结果 MCF-7/TAM细胞株对TAM敏感性显著降低,耐药模型构建成功;SIN和TAM均能够剂量依赖性地抑制MCF-7/TAM细胞的增殖,SIN干预能够显著增加MCF-7/TAM细胞对TAM的敏感性,经CompuSyn软件分析显示两药呈协同作用;SIN和TAM联合应用能够更显著地诱导MCF-7/TAM细胞凋亡和阻滞细胞周期;MCF-7/TAM细胞中PI3K、Akt和mTOR的磷酸化水平显著高于MCF-7细胞,经过SIN干预后MCF-7/TAM细胞中PI3K、Akt和mTOR的磷酸化水平显著下降。结论 青藤碱能够有效逆转MCF-7细胞对他莫昔芬耐药,其机制可能是通过抑制PI3K/AKT/mTOR信号通路发挥作用。     

PI3K/AKT/mTOR信号通路抑制剂在宫颈癌治疗中的研究进展

宫颈癌是女性常见恶性肿瘤之一。针对局部晚期及复发转移的宫颈癌患者尚未有令人满意的治疗手段,因此探索和发展更有效的治疗方案具有重要的意义。PI3K/AKT/m TOR信号通路在人类子宫颈癌细胞的增殖、分化和凋亡中具有重要的调节作用,有希望成为开发宫颈癌治疗药物的新型靶标。综述了近年来PI3K/AKT/m TOR信号通路的单一及双重靶点抑制剂针对宫颈癌的临床前及临床研究情况,包括PI3K抑制剂(wortmannin、LY294002、吲哚-3-甲醇)、AKT抑制剂(SC-66、MK-2206、木黄酮、冬凌草甲素和雷公藤)、m TOR抑制剂(替西罗莫司和依维莫司)及双重靶点抑制剂(GSK2126458、BEZ235、BGT226、PF04691502、GDC-0980和PKI-587)等。     

磷脂酰肌醇-3磷酸激酶/AKT/雷帕霉素靶蛋白信号通路参与中枢神经损伤保护与修复的研究进展

中枢神经细胞对各种损伤刺激耐受差,损伤后神经修复困难.因此促进神经保护增强神经再生能力已成为神经治疗关键.磷脂酰肌醇-3磷酸激酶/AKT/雷帕霉素靶蛋白(PI3K/AKT/mTOR)信号通路是调节细胞周期的重要通路,在细胞增殖、生长、分化过程中起中心调控作用,在神经损伤过程中通过激活PI3K/AKT/mTOR信号通路可减少神经细胞死亡,促进神经修复.该文对PI3K/AKT/mTOR信号通路在中枢神经损伤保护作用、修复机制及可能风险作一综述,探讨将PI3K/AKT/mTOR信号通路作为靶点治疗中枢神经疾病.     

Targeting the PI3K signaling pathway in cancer therapy

INTRODUCTION: The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. The pathway is frequently active in many different types of cancer-e.g., breast, bladder, prostate, thyroid, ovarian and NSCLC. Targetable genetic aberrations in this pathway give us many opportunities for development of targeted therapies for different types of cancer. AREAS COVERED: The genetic alterations in the PI3K/mammalian target of rapamycin (mTOR)/Akt pathway, as well as the drugs that target this pathway, either alone, in combination with other targeted agents or in chemotherapy. Targeted inhibitors of the PI3K pathway currently being tested in clinical trials in different types of human cancer. EXPERT OPINION: Small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway show some success with these agents in current clinical trials. For further improvement in response, molecular correlates that can be used for patient selection, need to be determined. A more efficient and effective way to screen for patients to determine which patients are most likely to benefit from PI3K pathway inhibitors is also needed.