ROS1 is a receptor tyrosine kinase (RTK) of the insulin receptor family. Chromosomal rearrangements
involving the ROS1 gene, on chromosome 6q22, were originally
described in glioblastomas (e.g., FIG-ROS1; Birchmeier,
Sharma, and Wigler 1987; Birchmeier
et al. 1990; Charest
et al. 2003). More recently, ROS1 fusions were identified as a potential
"driver" mutation in non-small cell lung cancer (Rikova
et al. 2007) and cholangiocarcinoma (Gu et al. 2011).
ROS1 fusions contain an intact tyrosine kinase
domain. To date, those tested biologically possess oncogenic activity (Charest
et al. 2003; Rikova
et al. 2007). Signaling downstream of ROS1 fusions results in activation of
cellular pathways known to be involved in cell growth and cell proliferation (Figure 1).
ROS1 fusions are associated with sensitivity in vitro to tyrosine kinase inhibitors that
inhibit ROS1 (McDermott et al. 2008).
Schematic representation of ROS1 fusions. "X" represents the various fusion partners that
have been described. Dimerization of the
ROS1 fusion mediated by the fusion partner ("X"), results in constitutive activation of the
ROS1 tyrosine kinase. ROS1 signaling
results in pro-growth and anti-apoptosis effects.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ROS1. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
ROS1 in Non-Small Cell Lung Cancer (NSCLC)
Approximately 2% of lung tumors harbor ROS1 fusions (Bergethon et al. 2012).
Like ALK fusions, ROS1 fusions are more commonly found in light smokers (<10 pack years)
and/or never-smokers. ROS1 fusions are also associated with younger age and adenocarcinomas
(Bergethon et al. 2012).
In preclinical models, ROS1 fusions are associated with sensitivity to tyrosine kinase inhibitors that have 'off-target'
activity against ROS1, such as crizotinib (Bergethon et al. 2012; Davies et al.
2012). In addition, two patients—a previously treated metastatic
NSCLC patient and a 65-year-old never smoker NSCLC patient—with tumors harboring
ROS1 fusions have had partial responses to crizotinib (Bergethon et al. 2012; Davies et al.
2012). In an expansion cohort of a phase I study, 50 patients with ROS1-positive
NSCLC demonstrated a 72% response rate and 19.2-month median progression-free survival
interval when treated with crizotinib (Ou et al.
2013; Shaw et
al. 2014). In a European case study, 32 ROS1-positive NSCLC cases treated
with crizotinib were retrospectively reviewed, and an 80% response rate and a 9.1-month
median progression-free survival interval was calculated in this cohort (Mazières
et al. 2015).
Several different ROS1 rearrangements have been described in NSCLC. These include
SLC34A2-ROS1, CD74-ROS1, EZR-ROS1, TPM3-ROS1, and SDC4-ROS1 (Figure
1; Davies et al.
2012; Rikova et al. 2007; Takeuchi et al.
2012). Clinically, the presence of a ROS1 rearrangement is detected by fluorescence
in situ hybridization (FISH) with a ROS1 breakapart probe. FISH testing is not able to
discern which particular ROS1 fusion is found in a clinical sample.
ROS1 rearrangements are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, KRAS mutations,
ALK fusions, etc.; Bergethon et al. 2012).
Figure 1. Schematic representation of
ROS1 fusions found in lung cancer.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ROS1 in Non-Small Cell
Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ros1/
(Updated November 17).
Last Updated: November 17, 2015
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