Department of Gastrointestinal Surgery, Peking University Peoplès Hospital, Beijing, PR China.
Laboratory of Surgical Oncology, Peking University Peoplès Hospital, Beijing, PR China.
Scand J Gastroenterol. 2022 Nov;57(11):1334-1343. doi: 10.1080/00365521.2022.2087475. Epub 2022 Jun 18.
A gastrointestinal stromal tumor (GIST) is mostly driven by the auto-activated, mutant receptor tyrosine kinase gene or by the platelet-derived growth factor receptor alpha. Inhibition of -signaling is the primary molecular target therapy for GIST, which is performed by the drug imatinib clinically. However, more than half of advanced or metastatic GIST develop secondary resistance to imatinib within 2 years after initiation of treatment, and the mechanism of acquired imatinib-resistant in GIST remains unclear. Therefore, we designed the present study, and firstly analyzed the gene expression profile of imatinib-resistant and sensitive GIST from GEO DataSet and identified 44 differential expressed genes. Then, a model including nine genes with their expressed coefficients was identified as a risk score to predict imatinib-resistant GIST. Internal and external validation of the prediction model was performed through the ROC curve, and the area under the curve was 0.967 (95%CI 0.901-1.000) and 0.917 (95%CI 0.753-1.000), separately. Lastly, the effect of immune, mA, pyroptosis, and ferroptosis-related genes on imatinib-resistant GIST was also assessed because DNA replication was the most enriched biological function of DEGs after functional annotation, pathway enrichment, and protein-protein interaction network analyses. In conclusion, the present study established a novel model to predict secondary imatinib-resistant GIST. Meanwhile, the bioinformatic mining results provided potential and promising targets for imatinib-resistant therapy.
胃肠道间质瘤（GIST）主要由自身激活的突变受体酪氨酸激酶基因或血小板衍生生长因子受体α驱动。-信号抑制是 GIST 的主要分子靶向治疗方法，临床上通过药物伊马替尼进行。然而，超过一半的晚期或转移性 GIST 在开始治疗后 2 年内对伊马替尼产生继发性耐药，GIST 获得性伊马替尼耐药的机制仍不清楚。因此，我们设计了本研究，首先从 GEO DataSet 分析了伊马替尼耐药和敏感 GIST 的基因表达谱，鉴定了 44 个差异表达基因。然后，确定了一个包含九个基因及其表达系数的模型作为预测伊马替尼耐药 GIST 的风险评分。通过 ROC 曲线对内、外部验证预测模型，曲线下面积分别为 0.967（95%CI 0.901-1.000）和 0.917（95%CI 0.753-1.000）。最后，还评估了免疫、mA、细胞焦亡和铁死亡相关基因对伊马替尼耐药 GIST 的影响，因为在功能注释、通路富集和蛋白质-蛋白质相互作用网络分析后，DEGs 最富集的生物学功能是 DNA 复制。总之，本研究建立了一种预测继发性伊马替尼耐药 GIST 的新模型。同时，生物信息学挖掘结果为伊马替尼耐药治疗提供了潜在的有希望的靶点。
