ROS1 is a receptor tyrosine kinase (RTK) of the insulin receptor family. Chromosomal rearrangements involving the ROS1 gene, on chromosome 6q22, were originally described in glioblastomas (e.g., FIG-ROS1; Birchmeier, Sharma, and Wigler 1987; Birchmeier et al. 1990; Charest et al. 2003). More recently, ROS1 fusions were identified as a potential "driver" mutation in non-small cell lung cancer (Rikova et al. 2007) and cholangiocarcinoma (Gu et al. 2011).
ROS1 fusions contain an intact tyrosine kinase domain. To date, those tested biologically possess oncogenic activity (Charest et al. 2003; Rikova et al. 2007). Signaling downstream of ROS1 fusions results in activation of cellular pathways known to be involved in cell growth and cell proliferation (Figure 1). ROS1 fusions are associated with sensitivity in vitro to tyrosine kinase inhibitors that inhibit ROS1 (McDermott et al. 2008).
Figure 1. Schematic representation of ROS1 fusions. "X" represents the various fusion partners that have been described. Dimerization of the ROS1 fusion mediated by the fusion partner ("X"), results in constitutive activation of the ROS1 tyrosine kinase. ROS1 signaling results in pro-growth and anti-apoptosis effects.