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).
1. 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
ROS1 Mutations Associated with Acquired Resistance to ROS1 TKI Therapy
|ROS1 Mutations Conferring Resistance to ROS1 TKI Therapy
||Location within the kinase domain
|G2032Ra (Awad et al. 2013)
|D2033Nb (Drilon et al. 2015)
|L2155Sc (Song et al. 2015)
|Implications for Targeted Therapeutics
|Response to crizotinib (ALK/MET/ROS1 TKI)
||Confers decreased sensitivitya,b,c
|Response to 2nd generation ROS1 TKIs
||Unknown at this timea,b,c
The mechanisms of acquired resistance in the setting of ROS1 fusions to the ALK/MET/ROS1 TKI,
crizotinib, are incompletely understood. However, case studies combined with supporting
preclinical data have suggested that missense mutations
within the ROS1 kinase domain can drive
acquired resistance to crizotinib. The mutations
described may confer variable degrees of sensitivity or resistance to other ROS1 TKIs (Davare et al. 2013,
Drilonet al. 2015,
al. 2015, Song
et al. 2015, and Zou et al. 2015).
A KIT activating mutation (KIT D816G;
Dziadziuszko et al.
2016) and EGFR pathway activation (Davies et al. 2013) have been
reported in two separate ROS1 fusion positive patients with acquired resistance to
crizotinib, demonstrating that activation of bypass signaling pathways may underlie crizotinib
a A patient with a crizotinib-sensitive NSCLC harboring a CD74-ROS1
fusion was found to have an acquired ROS1 G2032R mutation
at the time of progression (Awad et al. 2013). Residue G2032 is at
the solvent front of the kinase hinge, and arginine substitution at this position would create a
steric clash with crizotinib. In vitro data demonstrate that crizotinib has no effect on the
mutant CD74-ROS1 kinase activity, while non-mutant CD74-ROS1 kinase activity was inhibited (Awad et al. 2013).
However, preclinical data suggest that the next-generation ALK/MET/ROS1 inhibitors cabozantinib
al. 2015), foretinib (Davare et al. 2013), and
PF-06463922 (Zou et al. 2015)
are capable of overcoming this resistance mutation.
b A patient with crizotinib-sensitive NSCLC CD74-ROS1 fusion was
found to have an acquired ROS1 D2033N mutation
at the time of progression (Drilon et al. 2015). This mutation,
which is located at the solvent front of the kinase hinge, confers resistance to crizotinib but
not cabozantinib. The patient had a rapid clinical response to treatment with cabozantinib, with
a 92% reduction in disease burden by 12 weeks.
c Two HCC78 cell lines harboring the SLC34A2-ROS1 fusion that had
acquired crizotinib resistance (HCC78CR1 and HCC78CR2) were found to harbor the novel L2155S
mutation not present in the original cell line
(Song et al. 2015).
Ba/F3 cells lines expressing cDNA encoding CD74-ROS1 L2155S also showed resistance to foretinib
d This mutation was
identified in HCC78 cells with acquired crizotinib resistance. HCC78 harbor the
SLC34A2-ROS1 fusion (Davies et al. 2012).
Suggested Citation: Lovly, C. 2016. ROS1 Mutations
Associated with Acquired Resistance to ROS1 TKI Therapy. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ros1/346/
(Updated June 10).
Last Updated: June 10, 2016
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