ROS1( ROS1 lung cancer)

• 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.

ROS1 gene rearrangements define a distinct molecular subtype of NSCLC, occurring in approximately 1-2% of cases and frequently associated with younger age, non-smoker status, and a high incidence of brain metastases. 

It occurs when the ROS1 gene fuses with another gene, creating an “on” signal that drives uncontrolled cell growth.

It is highly treatable with targeted therapies that specifically block this signal.

It is more frequently found in younger adults, women, and individuals with little to no smoking history.

Most cases are adenocarcinomas.

Metastatic Potential: It has a high tendency to spread to the brain (present in up to 40% of patients at diagnosis).

Not Inherited: ROS1 rearrangements are somatic, meaning they occur randomly in lung cells during a person’s life and cannot be passed to children.

Treatment:

Standard treatment involves Tyrosine Kinase Inhibitors (TKIs), which are oral designed to shut down the overactive ROS1 protein.

Preferred FDA-approved first-line therapy options include crizotinib, entrectinib, repotrectinib or taletrectinib.

Taletrectinib (Ibtrozi) for adults with ROS1-positive locally advanced or metastatic NSCLC achieved a confirmed overall response rate of 90% in patients who had not previously received a TKI. 

For previously treated patients, for the 113 patients who had received previous treatment with ROS1 inhibitor drugs, taletrectinib’s response rate was 52–62% and lasted more than 6 months for most patients. 

Zidesamtinib has received FDA breakthrough therapy designation for patients with ROS1-positive metastatic NSCLC previously treated with 2 or more ROS1 TKIs.

Over time, the cancer may develop a resistance mutation — a gene change that causes it to stop responding to a certain drug.

Repotrectinib (Augtyro)-Preferred first-line; strong brain penetration and effective against common resistance mutations.

Entrectinib (Rozlytrek) | First-Gen | Specifically designed to cross the blood-brain barrier.

Crizotinib (Xalkori) | First-Gen | The first approved drug; highly effective but has lower brain penetration.

Taletrectinib (Ibtrozi) | Next-Gen-effective against resistance mutations with fewer neurological side effects.

Accurate diagnosis requires comprehensive biomarker testing, such as Next-Generation Sequencing (NGS) or FISH (Fluorescence In Situ Hybridization).

Over time, the cancer may develop new mutations (like G2032R) that make the first drug stop working, with switching to a next-generation TKI or a different treatment like chemotherapy.

Immunotherapy alone is less effective for ROS1+ cancers compared to other lung cancer types.

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.

Resistance to ROS1 tyrokinase inhibitors invariably occurs and causes disease relapse.

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.