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Πέμπτη 30 Μαΐου 2019

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.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.[7][8][9][10] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[8] 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.[7][11] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[12] Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[13][14] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.[15] 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.[16][17][18] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.[19][20] 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.[21][22][23] 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.[24] 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.

Biomarkers

Molecular markers used to guide treatment, assess prognosis, or detect relapse.

ROS1

In the Phase I/IB study, only patients with NTRK or ROS1 fusions, or an ALK fusion or mutation responded to entrectinib, while patients without these tumor markers didn’t respond.
In the JAMA study, researchers confirmed the previously known clinical and genomic features of NSCLC patients in their large clinico-genomics database.
The draft guidelines have intrigued industry players interested in pursuing labeling that would allow their CDx to direct treatment for a class of drugs instead of one drug.
The new guidelines said ROS1, KRAS, BRAF, MET, RET, and HER2 should be included in targeted and expanded panels.
Next year, the company will submit regulatory filings for the drug in two molecularly defined indications and a next-generation sequencing companion diagnostic. 
Patients are organizing themselves in groups based on the molecular features driving their tumors to better advocate for themselves, raise money, and influence research.
The changes include recommendations for first line immunotherapy in patients with high PD-L1 expression, and clarification on use of targeted therapies.
The so-called universal CDx approved by the FDA can gauge alterations across multiple genes associated with response to three lung cancer treatments. 
Data from the meeting suggest that lung cancer patients with ALK-positive tumors may soon have two first-line options and more choices when their disease progresses.
Genentech's Alecensa and AstraZeneca's Tegrisso are the latest precision lung cancer drugs, and Xalkori might soon be an option for a new molecular subpopulation.

Official Symbol
ROS1provided by HGNC
Official Full Name
ROS proto-oncogene 1, receptor tyrosine kinaseprovided by HGNC
Primary source
HGNC:HGNC:10261
See related
Ensembl:ENSG00000047936 MIM:165020
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
ROS; MCF3; c-ros-1
Summary
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. [provided by RefSeq, Jul 2008]
Expression
Restricted expression toward lung (RPKM 10.3) See more
Orthologs

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