Li Jian, Dang Yunzhi, Gao Jing, Li Yanyan, Zou Jianling, Shen Lin
Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
Med Oncol. 2015 Apr;32(4):111. doi: 10.1007/s12032-015-0554-6. Epub 2015 Mar 11.
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, phospho-AKT (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.
磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路的激活可能与伊马替尼耐药有关；然而，尚无研究关注该信号通路在伊马替尼耐药后信号传导是否会发生变化。本研究共纳入91例患者的111份胃肠道间质瘤（GIST）样本，其中包括20对伊马替尼治疗前后的样本。对组织进行免疫组化检测p-KIT（磷酸化KIT）、PTEN（第10号染色体缺失的磷酸酶及张力蛋白同源物）、PI3K、磷酸化AKT（p-AKT）、磷酸化4EBP1（p-4EBP1）和磷酸化S6（p-S6RP）。伊马替尼继发耐药的GIST中AKT/mTOR的激活率（53.1%）显著高于伊马替尼敏感（27.1%）和原发耐药的GIST（33.3%）（P = 0.049）。在对20对样本的分析中，将伊马替尼治疗前的GIST与治疗中的样本进行比较，8例伊马替尼治疗有效的患者和12例继发耐药的患者中，分别有4例PI3K状态从失活变为激活。8例伊马替尼治疗有效的患者治疗前和治疗中的样本AKT/mTOR状态为失活；然而，12例肿瘤进展患者中有6例状态从失活变为激活。在一些继发耐药的GIST中，p-KIT的阴性表达与PI3K信号通路和/或AKT/mTOR信号通路活性相关。GIST伊马替尼继发耐药后PI3K/AKT/mTOR信号通路可部分激活。在该信号通路中，AKT/mTOR的激活是一个更关键的因素，PI3K激活可能是继发耐药的早期环节。
