• What is ROS1?
  • ROS1 in Lung Cancer
  • ROS1 Fusions
  • 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 Fusions in Non-Small Cell Lung Cancer

Properties
Location of mutation Chromosomal rearrangements involving the ROS1 gene on 6q22
Frequency of ROS1 fusions in NSCLC ~2% (Bergethon et al. 2012)
Implications for Targeted Therapeutics
Response to crizotinib (ALK/MET/ROS1 TKI) Confers increased sensitivitya
Response to erlotinib/gefitinib (EGFR TKIs) Confers decreased sensitivityb
Response to cetuximab, panitumumab (anti-EGFR antibodies) Unknown​ at this time

ROS1 rearrangements are non-overlapping with other oncogenic mutations found in NSCLC (e.g., EGFR mutations, KRAS mutations, ALK fusions etc.; Rikova et al. 2007; Bergethon et al. 2012).

Preclinical studies show that cell lines harboring a ROS1 fusion are not sensitive to treatment with PF-04217903, a MET inhibitor (Davies et al. 2012).

a Crizotinib is approved by the FDA for non-small cell lung cancer with a ROS1 gene alteration (FDA 2016).

In case reports, 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 were calculated in this cohort (Mazières et al. 2015).

b Preclinical studies show that cell lines harboring a ROS1 fusion are not sensitive to treatment with EGFR TKIs (Davies et al. 2012McDermott et al. 2007McDermott et al. 2008Yasuda et al. 2012).

 

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # Patients in Study Response Rate PFS OS
Mazières et al. 2015 Retrospective analysis 1st line or greater crizotinib ROS1 + 32 80% 9.1  
Ou et al. 2013; Shaw et al. 2014 Phase I expansion cohort 1st line or greater crizotinib ROS1 + 50 72% 19.2 85% (12-month)
​NOTE: PFS = progression-free survival; OS = overall survival

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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. 2016. ROS1 Fusions in Non-Small Cell Lung Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ros1/67/ (Updated March 25).

Last Updated: March 25, 2016

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