Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies.
Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies.
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DOI：
10.1002/ajmg.c.31531
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Martinez-Agosto JA
中科院分区：
文献类型：
--
作者：
Keppler-Noreuil KM;Parker VE;Darling TN;Martinez-Agosto JA
磷脂酰肌醇-3-激酶 (PI3K)/AKT/mTOR 信号通路在调节正常细胞生长、代谢和存活中发挥着重要作用。 PI3K/AKT/mTOR 通路中的体细胞激活突变是癌症中最常见的突变之一，并已被证明会导致一系列过度生长综合征，包括 PIK3CA 相关过度生长谱、变形杆菌综合征和大脑过度生长状况。这些疾病的临床表现可能是孤立的或多重的，包括散发性或镶嵌性过度生长（脂肪、骨骼、肌肉、大脑、血管或淋巴）和皮肤异常（包括表皮痣、色素过度和色素减退病变），并具有潜在的肿瘤发生风险。 PI3K-AKT 信号通路的关键负调节因子包括 PTEN 和 TSC1/TSC2，这些基因的种系功能丧失突变可导致 PTEN 错构瘤肿瘤综合征和结节性硬化症。这些条件的镶嵌形式导致受影响位点的 PI3K 和 mTOR 激活增加，并且这些条件之间存在表型重叠。所有这些都与显着的发病率相关，除了对症治疗和手术之外，治疗选择有限。由于 PI3K/AKT/mTOR 通路失调与癌症有关，因此针对 PI3K/AKT/mTOR 信号通路不同成分的几种小分子抑制剂正在临床研究中。这些疗法的发展使靶向治疗体细胞 PI3K/AKT/mTOR 相关过度生长综合征的前景更加接近。这篇综述描述了这些嵌合体过度生长综合征的临床发现、基因功能和发病机制，并提出了现有和未来的治疗策略，以减少或预防这些疾病的相关并发症。
The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are amongst the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper- and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders.
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影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
7.5
作者：
Dazert, Eva;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
9.9
作者：
Crino, Peter B.;Aronica, Eleonora;Nathanson, Katherine L.
通讯作者：
Nathanson, Katherine L.
影响因子：
8.8
作者：
Chen ZH;Zhu M;Yang J;Liang H;He J;He S;Wang P;Kang X;McNutt MA;Yin Y;Shen WH
通讯作者：
Shen WH
影响因子：
11.2
作者：
D'Gama, Alissa M.;Geng, Ying;Couto, Javier A.;Martin, Beth;Boyle, Evan A.;LaCoursiere, Christopher M.;Hossain, Amer;Hatem, Nicole E.;Barry, Brenda J.;Kwiatkowski, David J.;Vinters, Harry V.;Barkovich, A. James;Shendure, Jay;Mathern, Gary W.;Walsh, Christopher A.;Poduri, Annapurna
通讯作者：
Poduri, Annapurna