Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Cancer Cell. 2023 Feb 13;41(2):340-355.e6. doi: 10.1016/j.ccell.2023.01.007.
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.
需要有效的治疗策略来治疗表皮生长因子受体 (EGFR) 突变的非小细胞肺癌 (NSCLC) 患者，这些患者对 EGFR 酪氨酸激酶抑制剂 (TKI) 产生耐药性，这是由上皮-间充质转化 (EMT) 介导的。我们研究了可以通过抗体或过继细胞治疗方法靶向的细胞表面蛋白，并确定 CD70 在 EMT 相关耐药中高度上调。此外，CD70 的上调是耐药演变中的早期事件，并且发生在对药物耐受的持久性细胞 (DTPC) 中。CD70 促进细胞存活和侵袭性，刺激 CD70 可触发已知与获得性 TKI 耐药重新激活的信号转导途径。抗 CD70 抗体药物偶联物 (ADC) 和 CD70 靶向嵌合抗原受体 (CAR) T 细胞和 CAR NK 细胞对 EGFR TKI 耐药细胞和 DTPC 表现出强大的活性。这些结果表明 CD70 是具有获得性 EGFR TKI 耐药的 EGFR 突变肿瘤的治疗靶点，值得临床研究。
