肿瘤细胞治疗研究
英文原题：CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.
CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance.
对于因上皮-间质转化（EMT）介导而对 EGFR 酪氨酸激酶抑制剂（TKIs）产生获得性耐药的 EGFR 突变非小细胞肺癌（NSCLC）患者，需要有效的治疗策略。
对于表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）患者，若上皮-间质转化（EMT）介导的EGFR酪氨酸激酶抑制剂（TKI）耐药，需要有效治疗策略。本研究调查可通过抗体疗法或过继细胞疗法靶向的细胞表面蛋白，并鉴定出CD70在EMT相关耐药中显著上调。此外，CD70上调是耐药演化的早期事件，也发生于药物耐受持留细胞（DTPC）。CD70促进细胞存活和侵袭；刺激CD70会触发已知在获得性TKI耐药时重新激活的信号转导通路。抗CD70抗体药物偶联物（ADC）、靶向CD70的嵌合抗原受体（CAR）T细胞和CAR NK细胞，对EGFR TKI耐药细胞及DTPC均显示强效活性。这些结果鉴定CD70为获得性EGFR TKI耐药的EGFR突变型肿瘤治疗靶点，值得开展临床研究。
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.
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