摘要
磷酸肌醇3激酶AKT哺乳动物雷帕霉素靶标(PI3K-AKTmTOR)信号通路在胰腺癌(PC)的病因学中是重要的,并且在PC中经常被激活。然后与较差的预后相关联。这种途径的异常激活参与细胞代谢和存活,细胞周期进程,凋亡调节,蛋白质合成和基因组不稳定性。已经开发了几种药物来靶向Akt / PI3K途径,包括PI3K抑制剂(例如LY294002,渥曼青霉素),PI3K / mTOR抑制剂(例如BEZ235)或Akt抑制剂(例如perifosine,MK2206),其单独或在与胰腺导管腺癌(PDAC)中的DNA靶向剂(例如吉西他滨和氟尿嘧啶)的组合。然而,由于其不利的药物活性,毒性和其他脂质和蛋白激酶的交叉抑制,这些化合物尚未用于临床研究。在本次审查中,我们专注于开发用于临床应用的Akt,PI3K和mTOR抑制剂的进展,以及PDAC发展的需要以及对抗预防毒性的预测生物标志物和组合策略的鉴定抵抗治疗的机制。
关键词: PI3K-AKT途径,mTOR抑制剂,胰腺癌,耐药性,PDAC,生物标志物。
Current Medicinal Chemistry
Title:Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer
Volume: 24 Issue: 13
关键词: PI3K-AKT途径,mTOR抑制剂,胰腺癌,耐药性,PDAC,生物标志物。
摘要: The phosphoinositide 3 kinase AKT mammalian target of rapamycin (PI3K-AKTmTOR) signaling pathway is an important in the aetiology of pancreatic cancer (PC) and is frequently activated in PC. It is then associated with a poorer prognosis. Aberrant activation of this pathway is involved in cell metabolism and survival, cell cycle progression, regulation of apoptosis, protein synthesis, and genomic instability. Several agents have been developed to target the Akt/PI3K pathways, including PI3K inhibitors, (e.g. LY294002, Wortmannin), PI3K/mTOR inhibitors (e.g. BEZ235), or Akt inhibitors (e.g. perifosine, MK2206), which have been tested alone or in combinations with DNA-targeted agents (e.g., gemcitabine and fluorouracil) in pancreatic ductal adenocarcinoma (PDAC). However, due to their unfavorable pharmaceutical activities, toxicity, and crossover inhibition of other lipid and protein kinases, these compounds have not been used in clinical studies. In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.
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Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer, Current Medicinal Chemistry 2017; 24 (13) . https://dx.doi.org/10.2174/0929867324666170206142658
DOI https://dx.doi.org/10.2174/0929867324666170206142658 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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