The ROS-1 gene was discovered in the 1980s as the product of the avian sarcoma virus RNA UR2 (University of Rochester) [7]. This gene codes for 2347 amino acids that form a transmembrane protein sharing structural characteristics with the family of insulin receptors and ALK. The ROS-1 protein is composed of an extracellular domain containing a hydrophobic segment allowing transmembrane passage and an intracellular component containing a tyrosine-kinase domain with a terminal carboxyl [8]. Its physiological role is poorly understood but study results suggest that wild-type ROS is involved during embryonic development as an initiator of signaling events for the differentiation of epithelial tissues [9]. Early during the 2000s, the proto-oncogene role of ROS was first identified in brain tumors. A microdeletion in chromosome 6q21 is responsible for ROS-1 fusion with a new fused-in-glioblastoma (FIG) gene that is responsible for ROS-1 overexpression and production of signals abnormally activating the tyrosine-kinase pathway, conferring its proto-oncogene role [10]. In mouse models, FIG–ROS-1 transcript expression induces tumorigenesis and treatment with a small molecule, TAE684, inhibits growth of Baf3 cells overexpressing short and long isoform of FIG-ROS-1, thereby defining ROS-1 as an oncogenic “driver”.

The ROS-1 proto-oncogene role in lung cancer was first reported in 2007 by Rikova et al., who identified two other protein fusion transcripts: a transmembrane solute transporter (SLC34A2) and a type-2 transmembrane protein (CD74) [11]. Since then, improved sequencing techniques have enabled the discovery of increasing numbers of fusion partners [12,13], whose proto-oncogene roles in numerous cancers is now clearly established [14].

ROS-1 plays a major role in the activation of several signaling pathways associated with differentiation, proliferation, cell growth, and survival. ROS-1 rearrangement, by forming phosphotyrosine-recruitment sites in the terminal tail of ROS, causes kinase-activity deregulation of the protein and abnormal activation of signaling pathways, mediated by tyrosine-phosphatase tumor-suppressor SHP1/SHP2, pro-mitotic protein extracellular signal-regulated kinase (ERK1/2), insulin-receptor substrate (IRS-1), phosphatidylinositol 3-kinase (PI3K) pathway, protein kinase B (AKT), mitogen-activated protein kinases (MAPKs), signal transducer and activator of transcription (STAT3), and VAV3 [15]. However, the ligand binding to its recruitment site initiating ROS-protein activation remains unknown. Moreover, study results suggest that activation of the pathways could depend on the fusion transcript. Thus, in the case of CD74–ROS-1 fusion, the role played by phosphorylation of the E-Syt-1 (extended synaptotagmin-like) protein could confer the tumor cell with greater metastatic and invasive potential [16].

ROS-1 rearrangement is present in approximately 0.9–2.6% of NSCLCs [13,17,18,19,20]. Like ALK rearrangements, it is more frequent in young subjects, women and never-smokers [13,17,18,19,20]. ROS-1-positive NSCLCs are predominantly lepidic, acinar, or solid adenocarcinomas, with more than 90% expressing thyroid transcription factor-1 (TTF1), diagnosed at an advanced stage (stage III–IV), with a higher frequency of brain metastases [20,21,22,23,24]. More rarely, ROS-1 rearrangement is found in other histological subtypes, e.g., squamous-cell carcinomas, pleomorphic carcinomas or large-cell carcinomas [13,23,25,26,27]. Histological examination of these tumors mainly finds a solid architecture with round nuclei containing macronucleolus, “signet-ring cell”, and a close relationship with adjacent bronchioles [25]. Imaging shows metastatic lymph-node tropism, often reported with less frequent extrathoracic metastatic sites than for ALK rearranged or epidermal growth factor receptor (EGFR)-mutated NSCLCs [28]. Miliary forms of lung metastases have also been described [29]. Several authors reported a heightened thromboembolic risk of ROS-1-rearranged tumors compared with NSCLCs harboring non-rearranged ROS-1 [30], and even rarer cases of thrombotic microangiopathies [31] and disseminated intravascular coagulation [32]. Although the underlying mechanisms remain to be elucidated, interaction between extracellular carcinoid mucins secreted into the bloodstream and platelet (P-) and leukocyte (L-) selectins could trigger platelet activation and the formation of microthrombi responsible for thromboembolic events [33].