What is ROS1?
The ROS1 signaling pathway has been associated with cancer development1,2
- Genetic rearrangements of ROS1 have been identified in various cancer types and widely studied in non-small cell lung cancer (NSCLC)2
- While ROS1 is expressed in normal healthy
cells, it is not normally expressed in the lung2
- The role of ROS1 in normal development is not fully understood2
- ROS1 gene rearrangements are the primary drivers of disease in ROS1+ NSCLC2
The ROS1 signaling pathway1-4
AKT=v-akt murine thymoma viral oncogene homologue; ERK=extracellular signal-regulated kinase; JAK=Janus kinase; MEK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; NSCLC=non-small cell lung cancer; PI3K=phosphatidylinositol-4,5-bisphosphate 3-kinase; RAF=rapidly accelerated fibrosarcoma kinase; Ras=rat sarcoma kinase; ROS1=ROS proto-oncogene 1; STAT=signal transducer and activator of transcription.
ROS1 genetic rearrangements, both inter- and intra-chromosomal, lead to constitutive activation of the ROS1 kinase1-4
Genetic rearrangements in the tyrosine kinase receptor ROS1 lead to the development of fusion proteins2
For illustrative purposes.
- ROS1 fusion proteins are constitutively active and drive downstream signaling pathways such as AKT or MEK, depending on the ROS1 fusion partner2
- Constitutive activation of these signaling pathways can result in cell proliferation and tumorigenesis1,2
ROS1 fusion proteins are the primary oncogenic drivers in some patients with NSCLC2
- ROS1 rearrangements primarily occur in the absence of other known oncogenic drivers in NSCLC2
- The prevalence of ROS1 rearrangement in NSCLC is 1-2%. The majority of these cases exhibit adenocarcinoma histology2,5
- Approximately 20,000 patients worldwide are diagnosed with ROS1+ NSCLC per year2
ROS1+ NSCLC demonstrates metastatic potential in the CNS6
- It has been reported that up to 36% of patients with ROS1+
NSCLC have brain metastases at initial presentation. However, there
remains wide variability in the reported incidence of brain
metastases in this patient population.6-8 CNS metastasis
is associated with significant morbidity and poor survival9
- Substantial neurological impairment is common
- Median survival of untreated patients is 4 to 7 weeks
The blood-brain barrier creates a sanctuary for metastatic disease10
- Not all molecules can cross the blood-brain barrier. In order to cross, molecules need to be small and lipophilic10
- Of those that do cross, depending on their chemical structure, some small molecules are removed from the CNS after they pass through the blood-brain barrier through efflux activity10
- The blood-brain barrier is reinforced by P-gp, a drug-efflux-transporter protein, which actively removes a broad range of P-gp substrates from the endothelial cell cytoplasm before they cross into the CNS10
Transport routes in the blood-brain barrier11
Reprinted from NeuroRx, Vol 2/edition 1, Löscher
W, Potschka H. Blood-brain barrier active efflux transporters:
ATP-binding cassette gene family, 86-98, Copyright 2005, with
permission from Elsevier.
BCRP=breast cancer resistance protein; CNS=central nervous system; MRP=multidrug resistance protein; NSCLC=non–small cell lung cancer; Pgp=P-glycoprotein; ROS1=ROS proto-oncogene 1.
A mechanism found across species that protects the brain from exposure to toxins, both exogenous and endogenous.
Fluorescence in situ hybridization (FISH)
Fluorescence in situ hybridization infuses pieces of DNA with
fluorescent dye and adds them to a tissue sample, which can then be
analyzed to find specific genes on a chromosome, how many copies of
the gene are present, and any chromosomal abnormalities.
Uses antibodies to detect the target protein on tissue sections.
A transporter protein that serves as an efflux pump to extrude substrates back into circulation after they initially diffuse into the endothelial cells in the brain capillary.
Reverse transcriptase-polymerase chain reaction (RT-PCR)
Detects ROS1 by determining the presence of specific messenger RNA (mRNA) transcripts.
ROS proto-oncogene 1 (ROS1)
The ROS1 gene encodes a receptor tyrosine kinase in the insulin receptor superfamily. The role of ROS1 in normal development is not fully understood; however, genetic rearrangements of ROS1 have been identified in various cancer types and widely studied in non-small cell lung cancer.
Transposition of 2 segments between nonhomologous chromosomes as a result of abnormal breakage and refusion of reciprocal segments.
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