顺铂耐药是肺腺癌治疗失败的主要原因。耐药持久性（DTP）细胞是产生内在耐药性的原因，因为它们在最初的治疗周期中存活下来，成为显示获得性耐药性的克隆出现的储存库。尽管DTP细胞的分子机制已被描述，但很少有研究调查DTP细胞对顺铂内在耐药性的最早分子改变。在这项工作中，我们报告了与肺腺癌细胞系中顺铂-DTP 细胞的出现相关的基因表达特征。单次接触顺铂后，我们对顺铂-DTP 的转录组进行了测序，以鉴定差异表达的基因。生物信息学分析表明，早期顺铂-DTP 细胞会解除代谢和增殖途径的调节，以在药物损伤中生存。相互作用网络分析确定了三个高度关联的子模块，其中 SOCS1 在控制顺铂-DTP 细胞的增殖中发挥着重要作用。候选基因及其相应蛋白的表达在肺腺癌细胞系中得到验证。重要的是，CDDP 敏感和 CDDP 耐药肺腺癌细胞系中 SOCS1 的表达水平不同。此外，CDDP 耐药细胞系中 SOCS1 的敲低部分促进了其对 CDDP 的敏感性。最后，根据癌症基因组图谱中接受顺铂治疗的患者的总体生存率，对候选基因的临床相关性进行了计算机分析。生存分析表明所选基因的下调或上调与总体生存相关。获得的结果表明这些基因可以用作预测生物标志物或潜在靶标，以提高肺癌患者 CDDP 治疗的有效性。版权所有 © 2023 Chavez-Dominguez、Aguilar-Cazares、Perez-Medina、Avila-Rios、Soto-Nava 、门德斯-特诺里奥、伊斯拉斯-巴斯克斯、贝尼托-洛佩斯、加利西亚-贝拉斯科和洛佩斯-冈萨雷斯。

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.Copyright © 2023 Chavez-Dominguez, Aguilar-Cazares, Perez-Medina, Avila-Rios, Soto-Nava, Mendez-Tenorio, Islas-Vazquez, Benito-Lopez, Galicia-Velasco and Lopez-Gonzalez.