Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps"
Xu Wang1, Pu Wang1, Ying Liao1
1Cancer 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.
Abstract:
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".
Insights
Targeting essential genes in drug-resistant tumors using the "Evolutionary Trap" concept shows promise. PDPN CAR-T cells effectively eliminated resistant cells, suggesting a new strategy for overcoming tumor drug resistance.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Tumor drug resistance remains a significant clinical challenge.
- The
- Evolutionary Trap
- concept aims to target essential genes in resistant cells.
- Existing strategies face limitations due to lack of accessible drug targets.
Purpose of the Study:
- To investigate the feasibility of the
- Evolutionary Trap
- concept in overcoming tumor drug resistance.
- To identify novel targets for CAR-T cell therapy in drug-resistant tumors.
- To evaluate PDPN as a potential therapeutic target.
Main Methods:
- Development and testing of PDPN-specific CAR-T cells.
- In vitro and in vivo cytotoxicity assays against lapatinib-resistant tumor cells.
- Analysis of gene expression profiles in 21 different drug-resistant tumor cell lines.
Main Results:
- Lapatinib-resistant cells showed high expression of PDPN, a membrane protein not significantly expressed in normal tissues.
- PDPN CAR-T cells demonstrated significant cytotoxicity against lapatinib-resistant tumor cells.
- JAG1, GPC3, and L1CAM were identified as upregulated targets in various drug-resistant tumor cells, suitable for CAR-T therapy.
Conclusions:
- CAR-T cell therapy represents a feasible approach to overcome tumor drug resistance, building upon the
- Evolutionary Trap
- concept.
- PDPN is a promising target for treating lapatinib-resistant tumors.
- The findings broaden the application of the
- Evolutionary Trap
- strategy for diverse drug-resistant cancers.
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