ROS1

ROS1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3ZBF, 4UXL
Identifiers
Aliases	ROS1, MCF3, ROS, c-ros-1, ROS proto-oncogene 1, receptor tyrosine kinase
External IDs	MGI: 97999 HomoloGene: 2207 GeneCards: ROS1
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • kinase activity • protein binding • transmembrane receptor protein tyrosine kinase activity • protein tyrosine kinase activity • protein phosphatase binding • ATP binding Cellular component • integral component of membrane • membrane • plasma membrane • cell surface • perinuclear region of cytoplasm Biological process • cell differentiation • regulation of TOR signaling • signal transduction by protein phosphorylation • phosphorylation • transmembrane receptor protein tyrosine kinase signaling pathway • regulation of phosphate transport • negative regulation of gene expression • protein phosphorylation • cell growth • spermatogenesis • regulation of ERK1 and ERK2 cascade • peptidyl-tyrosine autophosphorylation • cell proliferation • columnar/cuboidal epithelial cell development Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6098	19886
Ensembl	ENSG00000047936	ENSMUSG00000019893
UniProt	P08922	Q78DX7
RefSeq (mRNA)	NM_002944	NM_011282
RefSeq (protein)	NP_002935.2	NP_035412.2
Location (UCSC)	Chr 6: 117.29 – 117.43 Mb	Chr 10: 52.05 – 52.2 Mb
PubMed search	[1]	[2]
Wikidata

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.^[3][4]

Function

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.^[4]

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.^[5][6][7][8] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.^[6] 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.^[5][9] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.^[10]

Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.^[11][12] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.^[13] 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.^[14][15][16] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.^[17][18] 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.^[19][20][21] 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.^[22] 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.^[23]

Preclinical findings

From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes.^[24] In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly-phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples.^[24] Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and ^[24] These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers.

Fusion prevalence

In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement.^[25] 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.^[25] 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.^[25] 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.^[9] 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.^[6] ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers.^[26]

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

• Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.
• Lorlatinib
• Ceritnib
• Merestinib

References

Further reading