对靶向药物的获得性耐药是癌症的主要挑战。耐药状态被认为是获得真正耐药性的第一步。据称，耐药持久性（DTP）细胞可以在治疗期间存活并保持休眠状态数年。单细胞测序可以提供 DTP 细胞基因表达的全面图谱，有助于研究耐药状态的异质性和识别新的抗癌靶点。通过整合基因表达综合 (GEO) 数据集来探索 DTP 的遗传图谱，并构建了 TCGA LUAD 队列肺腺癌中 DTP 相关基因 (DTPRG) 的预后特征。计算浸润免疫细胞的得分，并通过单样本基因集富集分析（ssGSEA）评估免疫相关通路的活性。对低风险组和高风险组之间的 DTPRG 进行功能富集分析。分析免疫细胞亚型和免疫相关通路。建立了11个基因panel（MT2A、UBE2S、CLTB、KRT7、IGFBP3、CTSH、NPC2、HMGA1、HNRNPAB、DTYMK和IHNA）。 DTPRGs 主要与核分裂、染色体分离和细胞周期途径相关。高危组的免疫细胞浸润较低，而高危组的炎症促进和 MCH I 类反应途径活性较高。生成具有预后准确性的列线图，并使用表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗后的临床结果进一步验证。构建了基于 DTPRG 的肺腺癌预后模型。靶向 DTP 细胞是预防耐药状态的潜在治疗方法。© 2023 作者。

Acquired resistance to targeted drugs is a major challenge in cancer. The drug-tolerant state has been proposed to be an initial step towards acquisition of real drug-resistance. Drug tolerant persister (DTP) cells are purported to survive during treatment and stay dormant for several years. Single cell sequencing can provide a comprehensive landscape of gene expression in DTP cells, which can facilitate investigation of heterogeneity of a drug tolerant state and identification of new anticancer targets.The genetic profiling of DTPs was explored by integrating Gene Expression Omnibus (GEO) datasets, and a prognostic signature of DTP-related genes (DTPRGs) in lung adenocarcinoma of TCGA LUAD cohort was constructed. The scores of infiltrating immune cells were calculated and activity of immune-related pathways was evaluated by single-sample gene set enrichment analysis (ssGSEA). Functional enrichment analysis of the DTPRGs between low- and high-risk groups was performed. Immune cell subtypes and immune-related pathways were analyzed.An 11-gene panel (MT2A, UBE2S, CLTB, KRT7, IGFBP3, CTSH, NPC2, HMGA1, HNRNPAB, DTYMK, and IHNA) was established. DTPRGs were mainly correlated with nuclear division, chromosome segregation, and cell cycle pathways. Infiltration of immune cells was lower in the high-risk group while the inflammation-promoting and MCH-class I response pathway had higher activity in the high-risk group. A nomogram was generated with prognostic accuracy, further validated using clinical outcomes following therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).A prognostic model of lung adenocarcinoma based on DTPRGs was constructed. Targeting DTP cells is a potential therapeutic approach to prevent a drug tolerant state.© 2023 The Authors.