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Abstract The therapeutic landscape in treating advanced oncogene-mutated non-small cell lung cancer (NSCLC) was revolutionized with the advent of tyrosine kinase inhibitors (TKIs). Despite the efficacious breakthrough and improved patient outcomes, disease progresses once more due to the seemingly inevitable development of drug resistance in tumor cells. This poses a considerable predicament in the clinical management of oncogene-mutated NSCLC and signifies the importance of elucidating the mechanism of resistance in tumor cells that harbor these genomic alterations which give rise to oncogenic drivers. Recent evidence suggests that drug-tolerant persister (DTP) cells, which are tolerant to initial exposure to TKIs give rise to acquired drug-resistant cells. Currently, the mechanism by which tumor cells undergo a drug-tolerant state is not well understood in NSCLCs driven by ALK or ROS1 fusion. Previously, we identified CD74 as a gene that may play a role in a drug-tolerant state in EGFR-mutated lung cancer via single-cell RNA-sequencing (scRNA-seq). Here, we sought to determine whether the CD74 signaling also leads to resistance to TKIs in NSCLCs with ALK or ROS1 fusion. We showed that CD74 expression increased at both the mRNA and protein levels after treatment with respective TKIs in ALK and ROS1 fusion cells lines. Notably, the ALK and ROS1 fusion cell lines also exhibited an increase in mRNA expression levels of upstream and downstream genes of CD74. Additionally, we generated CD74 knock-out and overexpression models in two cells lines, HCC78 (SLC34A2-ROS1 fusion) and H2228 (EML4–ALK fusion), to further examine the role of CD74 expression in DTP cells. We demonstrated that resistance to TKIs were dependent on CD74 expression. Furthermore, it was determined that anti-CD74 antibody-drug conjugates, in combination with TKIs, synergistically induced apoptosis in these cell lines. In conclusion, our data suggest that CD74 can be a therapeutic target in NSCLC with ALK or ROS1 fusion. Citation Format: Vivian Ho, Motohiro Izumi, Meghan Lee, Daisuke Shibahara, Ikei S. Kobayashi, Susumu S. Kobayashi. Elucidating the mechanism of resistance to tyrosine kinase inhibitors in ROS1-and ALK-fusion non-small cell lung cancer: The role of CD74 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3262.
Ho et al. (Fri,) studied this question.