癌症可以通过耐药持久性 (DTP) 细胞亚群的出现，对 ALK 酪氨酸激酶抑制剂 (ALK-TKI) 治疗产生耐药性，这些细胞可以在最初的药物治疗中存活足够长的时间以获得遗传畸变。因此，DTP 细胞是潜在的治疗靶点。我们从患者来源的 ALK 非小细胞肺癌 (NSCLC) 细胞系中生成了艾来替尼诱导的 DTP 细胞，并在抗癌化合物库 (TargetMol) 中筛选了 3114 种药物。我们发现磷脂氢过氧化物谷胱甘肽过氧化物酶 GPX4 参与促进 DTP 细胞的存活。研究发现 GPX4 在 DTP 细胞中表达上调，并通过抑制活性氧 (ROS) 积累来促进细胞存活； GPX4 抑制剂阻断这种上调并促进 ROS 介导的细胞死亡。在 DTP 细胞中还发现了涉及表皮生长因子受体 (EGFR)/受体酪氨酸蛋白激酶 erbB-3 (HER3) 的激活旁路信号，并且 EGFR-TKI 加 ALK-TKI 联合治疗可增强 ROS 水平。与单独使用每种药物相比，ALK-TKI 加旁路途径抑制剂加 GPX4 抑制剂的三重组合更能抑制细胞生长并诱导细胞内 ROS 积累。 ALK 抑制加上激活旁路信号抑制加上 GPX4 抑制的联合治疗可能是 ALK NSCLC 患者的一种有效治疗策略，可防止 ALK-TKI 产生耐药性并导致肿瘤根除。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK+ non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS-mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine-protein kinase erbB-3 (HER3) were also identified in DTP cells, and co-treatment with EGFR-TKI plus ALK-TKI enhanced ROS levels. Triple combination with an ALK-TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK+ NSCLC to prevent the development of resistance to ALK-TKIs and lead to tumor eradication.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.