*January 2025*
Drug-tolerant persister cells (DTPCs) are cancer cells that survive drug treatment such as tyrosine kinase inhibitors. These cells are a key reason why EGFR-positive NSCLC (EGFR+ NSCLC) can come back after treatment. 2023 EGFR Resisters/LUNGevity Foundation EGFR-positive Lung Cancer Research Awardees are studying how to target DTPCs.
Dr. Alexandre Reuben from the MD Anderson Cancer Center is researching how DTPCs in EGFR+ NSCLC affect immune system cells, particularly CD8+ T-cells, and exploring ways to eliminate these cells using T-cell therapies. Typically, EGFR+ NSCLC does not respond to currently approved immunotherapies, such as checkpoint inhibitors. CD8+ T-cells are specialized immune cells that recognize and kill cancer cells. The first goal of the project is to study how DTPCs, which survive cancer treatment, impact T-cells. Dr. Reuben’s team has analyzed the genetic makeup of DTPCs and found that DTPCs in EGFR+ NSCLC produce higher levels of certain molecules (IL-6 and IL-32) that could affect immune response by reducing the growth of T-cells. The second goal of the project is to explore how engineered T cells (TCR-T cells) might be used to kill DTPCs. The research team is using mouse models to test these engineered T-cells, to ensure that the T cells reach and stay in the tumors. These studies are laying the foundation for the potential use of such engineered T-cells to treat EGFR-positive NSCLC.
Dr. Susumu Kobayashi from the Beth Israel Deaconess Medical Center is using another approach to target DTPCs in EGFR+ NSCLC. His team has discovered that DTPCs in EGFR+ NSCLC produce the CD74 protein in high quantities. The CD74 protein helps with presenting antigens (foreign proteins) to immune cells and plays an important role in the immune system. This protein is found on the surface of DTPCs. Dr. Kobayashi’s project has multiple goals. First, the team is looking into how osimertinib treatment triggers the expression of CD74 in EGFR+ NSCLC. In their studies, they treated mice with osimertinib and found that EGFR+ NSCLC tumors initially shrank but later grew back and became resistant to osimertinib. The team found that CD74 protein expression remained high in the tumors that became resistant. This suggests that CD74 protein expression may help identify DTPCs in EGFR+ NSCLC. The researchers are now testing if targeting CD74-positive cells can prevent resistance to osimertinib. They are using two methods: genetic modification to remove CD74 and a drug that targets CD74 (CD74-ADCs). Initial experiments suggest that eliminating CD74 in mouse models of EGFR+ NSCLC leads to better responses to osimertinib treatment.
