The role of CD74 in the development of resistance to tyrosine kinase inhibitors in ROS1- and ALK-fusion non-small cell lung cancer
Date
2024
DOI
Authors
Ho, Vivian T.
Version
OA Version
Citation
Abstract
Although the utilization of efficacious tyrosine kinase inhibitors (TKIs) provides an encouraging push towards the treatment of non-small cell lung cancer (NSCLC) with oncogenic drivers, the development of drug resistance in tumor cells obstructs the path towards a permanent cure. The emergence of mechanisms of acquired drug resistance imposes a challenging hindrance in the clinical approach in addressing oncogenic-mutated NSCLC and indicates the need for further investigation on the signaling pathways that enable tumor cells to survive following the administration of TKIs. Previous studies have identified drug-tolerant persister (DTP) cells, a small population of tumor cells that develop tolerance to TKIs, may adapt to its environment and eventually promote the advancement of drug resistant tumor cells. Current understanding of the mechanism by which DTP cells emerge is limited, especially in ROS1- and ALK-rearrangement NSCLCs. In a prior study, single-cell RNA-sequencing (scRNA-seq) analysis was performed and detected CD74 as a potential DTP candidate gene that may allow cells to enter a DTP state in NSCLC harboring an EGFR¬ mutation. In this study, we assessed whether CD74 plays a role in the development of resistance to TKIs in HCC78 (SLC34A2-ROS1 fusion) and H2228 (EML4–ALK fusion) NSCLC cell lines. Our studies reveal upregulated levels in CD74 mRNA and protein expression, following TKI administration, in ROS1- and ALK-fusion cell lines. Additionally, our studies reveal an increase in mRNA expression of various upstream and downstream genes of CD74. The generation of CD74 knockout and overexpression models allow us to evaluate the function of CD74 in tumor cells that enter a drug-tolerant state. Here, our observation indicates that CD74 displays some influence in the development of resistance to TKIs. Additionally, the combination of TKIs with anti-CD74 antibody drug conjugates (ADCs) present a collective impact in triggering apoptosis in the HCC78 and H2228 cell lines. Overall, our studies demonstrate that CD74 may be a potential DTP candidate gene as well as a molecular target in ROS1- and ALK-fusion NSCLC.
Description
2024