美国德克萨斯大学安德森癌症中心John V. Heymach团队近期取得重要工作进展，他们研究发现CD70是EMT相关EGFR酪氨酸激酶抑制剂耐药性上调的治疗靶点。相关研究成果2023年2月13日在线发表于《癌细胞》杂志上。

据介绍，对于表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者，需要采取有效的治疗策略，这些患者通过上皮间质转化（EMT）介导对EGFR酪氨酸激酶抑制剂（TKIs）产生耐药性。

研究人员探明了可以通过基于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上调是耐药性演变的早期事件，并发生在药物耐受持久性细胞（DTPC）中。CD70促进细胞存活和侵袭性，CD70的刺激触发信号转导通路，已知信号转导通路被获得的TKI抗性重新激活。抗CD70抗体药物偶联物(ADC)，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显示出有效的活性。

总之，这些结果表明CD70是具有获得性EGFR TKI耐药性的EGFR突变肿瘤的治疗靶点，值得临床研究。

附：英文原文

Title: CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance

Author: Monique B. Nilsson, Yan Yang, Simon Heeke, Sonia A. Patel, Alissa Poteete, Hibiki Udagawa, Yasir Y. Elamin, Cesar A. Moran, Yukie Kashima, Thiruvengadam Arumugam, Xiaoxing Yu, Xiaoyang Ren, Lixia Diao, Li Shen, Qi Wang, Minying Zhang, Jacqulyne P. Robichaux, Chunhua Shi, Allyson N. Pfeil, Hai Tran, Don L. Gibbons, Jason Bock, Jing Wang, John D. Minna, Susumu S. Kobayashi, Xiuning Le, John V. Heymach

Issue&Volume: 2023/02/13

Abstract: Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC)patients with epidermal growth factor receptor (EGFR) mutations that acquire resistanceto EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition(EMT). We investigate cell surface proteins that could be targeted by antibody-basedor adoptive cell therapy approaches and identify CD70 as being highly upregulatedin EMT-associated resistance. Moreover, CD70 upregulation is an early event in theevolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transductionpathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibodydrug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell andCAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. Theseresults identify CD70 as a therapeutic target for EGFR mutant tumors with acquiredEGFR TKI resistance that merits clinical investigation.

DOI: 10.1016/j.ccell.2023.01.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00007-7