• What is ROS1?
  • ROS1 in Lung Cancer
  • ROS1 Mutations Resistant to ROS1 TKI Therapy
  • Clinical Trials

ROS1

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).

ros1.png

Figure 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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. ROS1. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ros1/?tab=0 (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. 2012Davies 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. 2012Davies 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. 2012Rikova 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).


ros1-nsclc.png

Figure 1.
Schematic representation of ROS1 fusions found in lung cancer.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

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
Mutation Location within the kinase domain ROS1 fusion
G2032Ra (Awad et al. 2013) Solvent front CD74-ROS1
D2033Nb (Drilon et al. 2015) Solvent front CD74-ROS1
L2155Sc (Song et al. 2015) Not reported SLC34A2-ROS1d
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, Katayama et 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 resistance.

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 (Katayama et 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 and NVP-TAE684.

d This mutation was identified in HCC78 cells with acquired crizotinib resistance. HCC78 harbor the SLC34A2-ROS1 fusion (Davies et al. 2012).

Contributors: Christine M. Lovly, M.D., Ph.D.

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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