ROS1 Fusions in Lung Cancer

MODELing human cancer in mice

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) is activated by chromosomal rearrangement in a variety of human cancers, including NSCLC, with occurrence in approximately 1% of NSCLC patients. The resulting ROS1 fusion kinases are constitutively activated and drive cellular transformation. In NSCLC, CD74–ROS1 is the most common ROS1 fusion (~44%), followed by EZR–ROS1 (16%). Interestingly, ROS1 fusions occur predominantly in lung adenocarcinomas in younger never smokers. ROS1-directed tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with treatment-naive advanced-stage ROS1 fusion-positive NSCLCs. However, intrinsic or extrinsic mechanisms of resistance to these inhibitors often occur. Therefore, there is an urgent need to tackle drug resistance to current ROS1 inhibitors, as well as to develop new therapeutic strategies to ROS1 fusions, particularly the potential of combining ROS1 inhibitors and immunotherapy. A preclinical mouse model, which has intact lung immune system, will be invaluable to achieve these goals. This proposal aims to establish the first humanized transgenic mouse model, which harbor the two most common ROS1 fusions, CD74–ROS1 and EZR–ROS1, as well as the most common resistance mutation in ROS1 (G2032R). Using these powerful mouse models we will study tumor initiation and progression. Furthermore, utilizing this model, we will characterize the tumor microenvironment associated with the ROS1 fusion, dissect the resistance mechanisms to ROS1 inhibitors, and identify new therapeutic strategies. 

IN COLLABORATION WITH:

Thales Papagiannakopoulos, NYU Langone Health

Kwok-Kin Wong, NYU Langone Health