Duan Yi, Haybaeck Johannes, Yang Zhihui
Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Cancers (Basel). 2020 Oct 14;12(10):2972. doi: 10.3390/cancers12102972.
Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of and gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
胃肠道间质瘤（GIST）起源于胃肠道肌间神经丛中的 Cajal 间质细胞（ICC）。大多数 GIST 是由于 基因的突变和 基因激活导致的，这些基因编码受体酪氨酸激酶（RTK）。RTK 抑制剂伊马替尼的临床应用显著改善了 GIST 患者的治疗；然而，伊马替尼耐药仍然是一个挑战。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）信号通路是肿瘤细胞增殖、凋亡、自噬和翻译的关键生存信号通路。RTK 的组成型自磷酸化会影响 PI3K/AKT/mTOR 信号通路的激活。在一些临床前和早期临床试验中，PI3K/AKT/mTOR 信号抑制被认为是一种有前景的 GIST 靶向治疗策略。目前，针对 PI3K/AKT/mTOR 信号通路不同部位的各种抑制药物正在进行 I 期和 II 期临床试验。本综述重点介绍了 GIST 中 PI3K/AKT/mTOR 依赖性机制的进展，并探讨了 mTOR 下游信号，特别是真核起始因子（eIFs）与 GIST 发生发展之间的关系，这可能有助于识别新的治疗靶点。
