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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

ROS1 callout signaling pathway

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

Gene fusion

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

Transport routes in the blood-brain barrier

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.

    B
    Blood-brain barrier

    A mechanism found across species that protects the brain from exposure to toxins, both exogenous and endogenous.

    F
    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.

    I
    Immunohistochemistry (IHC)

    Uses antibodies to detect the target protein on tissue sections.

    P
    P-glycoprotein

    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.

    R
    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.

    Reverse transcriptase-polymerase chain reaction (RT-PCR)

    Detects ROS1 by determining the presence of specific messenger RNA (mRNA) transcripts.

    T
    Translocation

    Transposition of 2 segments between nonhomologous chromosomes as a result of abnormal breakage and refusion of reciprocal segments.

    • Davies KD, Le AT, Theodoro MF. Clin Cancer Res. 2012;18(17):4570-4579. PMID: 22919003

      Davies KD, Le AT, Theodoro MF. Clin Cancer Res. 2012;18(17):4570-4579. PMID: 22919003

    • Davies KD, Doebele RC. Clin Cancer Res. 2013;19(15):4040-4045. PMID: 23719267

      Davies KD, Doebele RC. Clin Cancer Res. 2013;19(15):4040-4045. PMID: 23719267

    • Morgan GJ, He J, Tytarenko R, et al. Leukemia. 2018. PMID: 29654269

      Morgan GJ, He J, Tytarenko R, et al. Leukemia. 2018. PMID: 29654269

    • Zhu Y, Lin X, Li X, et al. Thorac Cancer. 2018;9(1):159-163. PMID: 28971587

      Zhu Y, Lin X, Li X, et al. Thorac Cancer. 2018;9(1):159-163. PMID: 28971587

    • Bergethon K, Shaw AT, Ou SH, et al. J Clin Oncol. 2012;30(8):863-870. PMID: 22215748

      Bergethon K, Shaw AT, Ou SH, et al. J Clin Oncol. 2012;30(8):863-870. PMID: 22215748

    • Gainor JF, Tseng D, Yoda S, et al. JCO Precis Oncol. 2017. PMID: 29333528

      Gainor JF, Tseng D, Yoda S, et al. JCO Precis Oncol. 2017. PMID: 29333528

    • Park S, Ahn BC, Lim SW, et al. J Thorac Oncol. 2018;13(9):1373-1382. PMID: 29883837

      Park S, Ahn BC, Lim SW, et al. J Thorac Oncol. 2018;13(9):1373-1382. PMID: 29883837

    • Patil T, Smith DE, Bunn PA, et al. J Thorac Oncol. 2018;13(11):1717-1726. PMID: 29981925

      Patil T, Smith DE, Bunn PA, et al. J Thorac Oncol. 2018;13(11):1717-1726. PMID: 29981925

    • Chi A, Komaki R. Cancers (Basel). 2010;2(4):2100-2137. PMID: 24281220

      Chi A, Komaki R. Cancers (Basel). 2010;2(4):2100-2137. PMID: 24281220

    • Deeken JF, Löscher W. Clin Cancer Res. 2007;13(6):1663-1674. PMID: 17363519

      Deeken JF, Löscher W. Clin Cancer Res. 2007;13(6):1663-1674. PMID: 17363519

    • Löscher W, Potschka H. NeuroRx. 2005;2(1):86-98. PMID: 15717060

      Löscher W, Potschka H. NeuroRx. 2005;2(1):86-98. PMID: 15717060

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