Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene. This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor.
Structure Proto-oncogene tyrosine-protein kinase ROS (ROS1) is a type I integral membrane protein and a member of the receptor tyrosine kinase (RTK) family. Structurally, it is a large protein composed of 2,347 amino acid residues and features a single transmembrane domain that anchors it to the plasma membrane. The extracellular region is responsible for ligand binding, whereas the intracellular region contains the tyrosine kinase domain, which catalyzes the phosphorylation of specific tyrosine residues in substrates. ROS1 shows a typical RTK organization: an extracellular ligand-binding domain, a single α-helical transmembrane segment, and a cytoplasmic domain containing the highly conserved ATP-binding and active sites required for kinase activity. The cytoplasmic segment also includes regions crucial for downstream signaling interactions.
Function Proto-oncogene tyrosine-protein kinase ROS (ROS1) is a receptor tyrosine kinase (RTK) that is evolutionarily conserved and involved in epithelial cell differentiation during organ development. Its precise physiological role in humans is not yet fully defined, but evidence suggests it functions in normal cellular signaling and developmental processes. Upon ligand binding (e.g., by NELL2), ROS1 activates several downstream cellular signaling pathways, contributing to epithelial cell differentiation, cell growth, and survival.
Clinical significance
Role in cancer
ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986. The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined. Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing. In 2016, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1-positive. Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines. In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient. Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1 tyrosine kinase inhibitors was effective in vitro. Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions. Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR. Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others. Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib.
Fusion prevalence In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement. ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease. ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs. Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history. A benefit of a small-molecule ALK, ROS1, and cMET inhibitor, crizotinib, was also shown in this patient group. ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions. Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors. ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers. Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012).
* Multiple variant isoforms observed CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3
As a drug target Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC). However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor.
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