Wang Xu, Wang Pu, Liao Ying, Zhao Xuan, Hou Rui, Li Sijin, Guan Zhangchun, Jin Yuhang, Ma Wen, Liu Dan, Zheng Junnian, Shi Ming
Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
College of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Pharmacol Res. 2024 Jun;204:107221. doi: 10.1016/j.phrs.2024.107221. Epub 2024 May 18.
Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".
基于“进化陷阱”的概念，靶向肿瘤耐药过程中获得的生存必需基因能够有效消除耐药细胞。然而，这一方法仍面临局限性。在本研究中，使用拉帕替尼耐药细胞来测试“进化陷阱”的概念，但由于所鉴定的基因没有可用药物，未找到合适的靶点。然而，一种在正常组织中低表达或不表达的膜蛋白PDPN，被鉴定为在拉帕替尼耐药肿瘤细胞中高表达。开发了PDPN CAR-T细胞，其在体外和体内对拉帕替尼耐药肿瘤细胞均表现出高细胞毒性，这表明CAR-T可能是基于“进化陷阱”克服肿瘤耐药性的一条可行途径。为了测试这一概念是否依赖于细胞系或药物，我们分析了21种耐药肿瘤细胞的表达谱，发现JAG1、GPC3和L1CAM作为CAR-T治疗的合适靶点，在各种耐药肿瘤细胞中均显著上调。我们的研究结果揭示了利用CAR-T疗法治疗耐药肿瘤的可行性，并拓宽了“进化陷阱”的概念。
