PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)
PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)
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DOI：
10.1007/s12032-015-0554-6
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发表时间：
2015-04-01
期刊：
影响因子：
3.4
通讯作者：
Shen, Lin
中科院分区：
文献类型：
--
作者：
Li, Jian;Dang, Yunzhi;Shen, Lin
磷脂酰肌醇-3-激酶（PI 3 K）/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）通路激活可能与伊马替尼耐药有关;然而，没有研究关注伊马替尼耐药后该通路的信号传导是否会改变。本研究共使用了91例患者的111份GIST样本，包括伊马替尼治疗前后的20对样本。对组织进行p-KIT（磷酸化-KIT）、PTEN（第10号染色体上缺失的磷酸酶和张力蛋白同源物）、PI 3 K、磷酸化AKT（p-AKT）、磷酸化-4EBP1（p-4 EBP 1）和磷酸化-S6（p-S6 RP）的免疫组织化学。伊马替尼继发性耐药GIST中AKT/mTOR的活化（53.1%）显著高于伊马替尼敏感GIST（27.1%）和原发性耐药GIST（33.3%）（P = 0.049）。在20对样本的分析中，比较伊马替尼治疗前和治疗中的GIST，PI 3 K状态从失活变为活化，分别在8例伊马替尼有效患者和12例发生继发性耐药的患者中各有4例。在伊马替尼有效的8例患者中，伊马替尼治疗前和治疗中样本中的AKT/mTOR状态为失活;然而，在肿瘤进展时，6例患者的状态从失活变为激活，12例患者为激活。p-KIT阴性表达的GIST中，PI 3 K通路和/或AKT/mTOR通路活性增高。GIST患者伊马替尼继发耐药后PI 3 K/AKT/mTOR通路部分激活。在该通路中，AKT/mTOR的激活是更为关键的因素，PI 3 K的激活可能是继发性耐药的早期部分。
Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway activation may be related to imatinib resistance; however, no study has focused on whether signal conduction of this pathway will change after imatinib resistance. A total of 111 GIST samples from 91 patients were used in this study, including 20 pairs of samples before and after imatinib treatment. Immunohistochemistry was performed on tissue for p-KIT (phospho-KIT), PTEN (phosphatase and tensin homolog deleted on chromosome ten), PI3K, phosphoAKT (p-AKT), phospho-4EBP1 (p-4EBP1) and phospho-S6 (p-S6RP). The activation of AKT/mTOR was significantly higher in imatinib secondary resistant GIST (53.1 %) than in imatinib-sensitive (27.1 %) and primary resistant GIST (33.3 %) (P = 0.049). In the analysis of 20 pairs of samples, comparing pre-imatinib GIST with on-treatment ones, the PI3K status was changed from inactivated to activated in four cases each in eight patients with effective imatinib and 12 patients whose secondary resistance happened, respectively. AKT/mTOR status was inactivated in pre-imatinib and on-treatment samples in eight patients with effective imatinib; however, the status of six patients was changed from inactivated to activated in 12 patients at the time of tumor progression. The negative expression of p-KIT was accompanied with PI3K pathway and/or AKT/mTOR pathway activity in some GISTs with secondary resistance. PI3K/AKT/mTOR pathway can be partly activated after imatinib secondary resistance in GIST. In this pathway, activation of AKT/mTOR is a more crucial factor, and PI3K activation may be the early part of secondary resistance.