TRSC-06 Characterization of a Non-Small Cell Lung Cancer Ros1-Fusion Brain Metastasis Model

BACKGROUND Non-small cell lung cancer (NSCLC) represents 85 percent of all lung cancers. Among NSCLC patients, 1-2 percent harbor mutations in the ROS1 proto-oncogene (ROS1). The most prevalent fusion mutations observed include SLC34A2-, CD74- and EZR-ROS1. Approximately 30 percent of the NSCLC patients with these ROS1 fusions develop brain metastases over time, posing significant challenges in treatment efficacy, due to the blood-brain barrier (BBB). ATP-binding cassette (ABC) transporters in the BBB restrict the penetration of compounds into the brain, reducing treatment effectiveness. To address this critical gap in treatment efficacy, a model that accurately mimics NSCLC brain metastases might be of great value. Currently, no SLC34A2-ROS1 driven intracranial tumor model exists, which might limit the clinical development of targeted agents in ROS1-fusion brain metastases. Therefore, the development and characterization of a mouse intracranial brain tumor model utilizing HCC78 cells, which have an intrinsic ROS1-SLC34A2 fusion, could provide valuable insights into targeted therapy efficacy and enhance understanding of NSCLC disease progression. METHOD The publicly available HCC78 cells will be transduced with a mCherry-Luciferase tag, to enable tumor growth visualization over time. Nude FVB mice will be injected with 250.000 HCC78 cells intracranially. Tumor growth will be assessed using IVIS imaging and MRI scanning. When the tumor size reaches its endpoint, the mice will be sacrificed and perfused with Texas Red. The brain will be stained for different markers, to assess tumor proliferation, immune infiltration, ROS1 status and the presence of ABC-transporters. RESULTS Preliminary results show that HCC78 cells are able to grow intracranially. No significant side effects have been observed in the mice. Further characterization of this model is ongoing.