*January 2025*
2021 EGFR Resisters/LUNGevity Foundation EGFR-positive Lung Cancer Research Award – Dr. Christine Lovly progress update
Dr. Christine Lovly from Vanderbilt University is studying how EGFR+ NSCLC cells become resistant to osimertinib, a tyrosine kinase inhibitor currently used as the first treatment option for EGFR+ lung cancer. Specifically, her laboratory is investigating how drug-tolerant persistent cells (DTPCs) play a role in resistance to osimertinib. 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. Her team is using advanced techniques, such as single-cell RNA sequencing (scRNAseq), to profile the genetic changes in DTPCs under treatment with osimertinib. They have studied four different EGFR-mutant lung cancer cell lines, analyzing how the gene expression evolves after treatment with osimertinib at various time points. They have found that a protein called CD74 is produced in large amounts by DTPCs. CD74 is a cell surface protein, i.e. it is found on the outside of cells, making it an attractive target both as a biomarker and as a drug target for DTPCs. Dr. Lovly’s laboratory is continuing to investigate how to target CD74.
Note: Dr. Susumu Kobayashi, a 2023 EGFR Resisters/LUNGevity Foundation EGFR-positive Lung Cancer Research Awardee, has also found that DTPCs from EGFR+ NSCLC produce high amounts of CD74 protein. This is an independent validation of Dr. Lovly’s work and highlights the importance of funding research that both identifies and validates new drug targets.
2021 EGFR Resisters/LUNGevity Foundation EGFR-positive Lung Cancer Research Award – Dr. Helena Yu final progress update summary
Dr. Helena Yu from Memorial Sloan Kettering Cancer Center is studying how EGFR+ NSCLC changes into other types of lung cancer after treatment with EGFR tyrosine kinase inhibitors. As a mechanism of resistance to EGFR inhibitors, cancers can change types from adenocarcinoma to small cell lung cancer (SCLC) or squamous cell lung cancer. Once this happens, EGFR inhibitors are no longer effective treatment; there are no strategies currently available to prevent or reverse transformation after it has occurred. Dr. Yu’s team has shown that mutations in the APOEBC genes (APOBEC mutational signatures) are common in EGFR-positive lung adenocarcinomas. These mutations may contribute to histologic transformation as well as other mechanisms of acquired resistance. These findings have been encapsulated in a manuscript (PMID: 36089134). Dr. Yu has also received an R01 grant totaling $1.25M from the National Cancer Institute based on preliminary data collected through the EGFR Resisters/LUNGevity grant. In addition, Dr. Yu is planning to start clinical trials for transformed EGFR+ NSCLC.
