ROS1 fusions  include the kinase domain containing region of ROS1 fused to various upstream partners, the most common of which is CD74.
The resultant oncoprotein has a kinase activation, increase downstream signaling, and tumor growth.
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-is 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

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

ROS1 can lead to the formation of oncogenic fusion proteins with kinase activity.

ROS1 rearrangements are identified in approximately 1-2% of patients with non-small cell lung cancer.

Proto-oncogene tyrosine-protein kinase ROS1 is highly expressed in a variety of tumor cell lines, belongs to the 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 which is encoded by the gene ROS1.

ROS1 has structural similarity to the anaplastic lymphoma kinase (ALK) protein.

ROS1 encoded by the c-ros oncogene.

The role of ROS1 protein in normal development, has not been defined.

The gene rearrangement events involving ROS1 are present in lung and other cancers, and have been found to be responsive to small molecule tyrosine kinase inhibitors.

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 have demonstrated an incidence of approximately 1% in non-small cell lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by ROS1 tyrosine kinase inhibitors was effective in vitro.

Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.

There are multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR.

Acquired resistant mutations develop in at least 50% of patients treated with ROS1 tyrosine kinase inhibitors in non-small cell lung cancer, and limited durability of the response: agents include crizotonib,and entrectinib.

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 besides NSCLC, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others.

Up to 36% of patients with ROS1 fusion positive non-small cell lung cancers have brain metastasis at the diagnosis of advanced disease, and many others will subsequently develop intracranial metastases.

In patients with NSCLC, approximately 2% are positive for a ROS1 gene 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.

ROS1 expression is found in approximately 2% of NSCLC patients, and its expression is limited to those patients with ROS1 gene fusions.

Crizotinib is it therapy of choice for advanced ROS1 rearranged NSCLC without CNS metastasis, while entrectinib  is the preferred option for those with CNS metastases.

The phase 1/2 TRIDENT-1 study, repotrectinib elicited an objective response rate (ORR) of 79% in TKI-naive patients and the median duration of response (DOR) was 34.1 months. 

ROS1 rearrangements in NSCLC typically is associated with younger age, light smoking history or never smokers, and adenocarcinoma histologic subtype.
Occasionally, ROS1 rearrangements have been seen in large cell and in squamous cell carcinoma‘ps of the lung.
ROS1 lung cancer is associated with a higher rates of venous thromboembolism.
Approximately 30% of patients with ROS1 experience  CNS metastasis during first line treatment with crizotinib, making serious CNS the most common side of disease progression in this population.
Repotrectinib abnext generation ROS1 tyrosine kinase inhibitor demonstrated clinical activity in patients with ROS1 fusion, positive non-small cell lung cancer: response rate was 79% in a phase 1 trial.

Immunohistochemical testing is used is used to establish the diagnosis of ROS1 positive NSCLC and confirmed with fluorescent insitu hybridization assay or next generation sequencing.

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