What is ROS1?

ROS1 genetic rearrangements, both inter- and intra-chromosomal, lead to constitutive activation of the ROS1 kinase^1-4

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 tumorigenesis^1,2

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 histology^2,5
• 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.