Abstract The oncogenic fusion CD74-ROS1 is a genetic alteration found in a small subset of patients diagnosed with non-small cell lung cancer (NSCLC). This fusion can promote cancer progression in these individuals at both early and late stages, making it an attractive therapeutic target when the standard treatment plans fail. Currently, CD74-ROS1 is targeted with tyrosine kinase inhibitors (TKIs), which inhibit the activity of ROS1. Nevertheless, drug resistance often occurs leaving patients with no alternative therapeutic options. Because CD74-ROS1 is particularly aggressive, supporting the formation of metastatic lesions, dissecting the roles of each fusion partner is of great importance for understanding the biological mechanisms that drive its cancer-promoting properties. Our work focuses on the establishment and characterization of methodically designed CD74-ROS1 variants expressed in the A549 lung adenocarcinoma cell line. The goal is to advance our understanding of the individual and cooperative functions of CD74 and ROS1 in the context of the CD74-ROS1 fusion. Next-generation sequencing (NGS) analysis revealed distinct gene expression profiles across the different transfectants, while phospho-kinase analysis further supports the idea that each protein partner possesses unique functional features. This study aids the efforts in understanding the functionality of CD74-ROS1 positive NSCLC, providing at the same time new biological targets for future signaling studies and therapeutic targeting. Citation Format: Jasmine Vargas, Julia Olivieri, Georgios Pantouris. Next-generation sequencing and phospho-kinase analysis expose partner-specific profiles in CD74-ROS1 fusions abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 349.
Vargas et al. (Fri,) studied this question.