Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps "

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".