需要有效的治疗策略来治疗表皮生长因子受体（EGFR）激酶抑制剂（TKIs）介导的上皮向间充质转化（EMT）引起EGFR突变的非小细胞肺癌（NSCLC）患者所具有的耐药性。我们研究了可通过抗体或免疫细胞治疗方法靶向的细胞表面蛋白，并鉴定CD70在EMT相关的耐药性中高度上调。此外，CD70上调是耐药演化的早期事件，出现在耐药持久细胞（DTPCs）中。CD70能促进细胞存活和侵袭，并且激活CD70可触发已知随着获得TKI抗药性而再次激活的信号转导通路。抗CD70抗体药物联合物（ADCs）和CD70靶向嵌合抗原受体（CAR）T细胞和CAR NK细胞对EGFR TKI抗药细胞和DTPCs表现出强效活性。这些结果确定CD70是EGFR突变肿瘤的治疗靶点，值得进行临床研究。版权所有©2023，由Elsevier Inc.发表。

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.Copyright © 2023. Published by Elsevier Inc.