Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway.
Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway.
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DOI：
10.1038/s41419-017-0132-2
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发表时间：
2018-01-26
影响因子：
9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Chen D;Lin X;Zhang C;Liu Z;Chen Z;Li Z;Wang J;Li B;Hu Y;Dong B;Shen L;Ji J;Gao J;Zhang X
紫杉醇（PTX）广泛应用于胃癌（GC）的一线化疗，但耐药性限制了其应用。由于缺乏合适的模型，GC中PTX耐药的机制尚未得到很好的研究。利用已建立的PTX抗性胃癌细胞亚系HGC-27 R，我们首次整合了胃癌PTX抗性的生物学特性和分子机制。数据显示，PTX耐药GC细胞的特征在于微管疾病、EMT表型、对抗有丝分裂药物的反应降低和对细胞凋亡的抗性（分别通过响应于抗有丝分裂药物或细胞凋亡诱导剂的β-微管蛋白III、波形蛋白的上调、G2/M分子或促细胞凋亡因子的减弱变化来标记）。磷酸肌醇3-激酶、丝氨酸/苏氨酸激酶Akt、哺乳动物雷帕霉素靶蛋白（PI 3 K/Akt/mTOR）和丝裂原活化蛋白激酶（MAPK）通路也被激活，这可能是上述表型改变的原因。体外数据表明，靶向这些途径足以在PTX耐药GC中引发抗肿瘤反应，其中双重PI 3 K/mTOR抑制剂BEZ 235显示出比mTOR抑制剂依维莫司或MEK抑制剂AZD 6244更高的治疗效率。BEZ 235的抗肿瘤作用也在荷HGC-27 R肿瘤的小鼠中得到证实。因此，这些数据表明，PI 3 K/Akt/mTOR和MAPK通路的抑制，特别是PI 3 K/mTOR双重阻断，可能是一个有前途的治疗策略，对PTX耐药的GC。
Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G2/M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.
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