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A Blood-based Test for the Detection of ROS1 and RET Fusion Transcripts from Circulating Ribonucleic Acid Using Digital Polymerase Chain Reaction
Published on: April 5, 2018
Identifying and targeting ROS1 gene fusions in non-small cell lung cancer
Kurtis D Davies1, Anh T Le, Mariana F Theodoro
1Division of Medical Oncology, University of Colorado, MS 8117, 12801 E. 17th Ave, Aurora, CO 80045, USA.
Purpose:
Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets.
Experimental Design:
An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting.
Results:
In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1 fusion, whereas two TMA samples expressed the CD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival.
Conclusions:
ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes.
Insights
ROS1 gene fusions drive non-small cell lung cancer (NSCLC). Targeting these fusions with inhibitors like crizotinib shows promise, leading to tumor shrinkage and inhibited cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Oncogenic gene fusions involving ROS1 kinase are implicated in various human cancers.
- Identifying and targeting these fusions is crucial for developing novel cancer therapies.
Purpose of the Study:
- To characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC).
- To evaluate ROS1 fusion proteins as potential drug targets for NSCLC treatment.
Main Methods:
- Screening of 447 NSCLC tissue samples and 48 patients for ROS1 rearrangement using FISH.
- Identification of fusion partners via inverse PCR and RT-PCR.
- Assessment of ROS1 inhibitor efficacy (crizotinib) in a patient and HCC78 cell line.
Main Results:
- ROS1 rearrangement detected in 1.2% of NSCLC samples and 1 of 48 patients.
- Identified ROS1 fusions include SDC4-ROS1, CD74-ROS1, and SLC34A2-ROS1.
- Crizotinib treatment led to tumor shrinkage in a patient and antiproliferative effects in cell lines.
Conclusions:
- ROS1 inhibition represents a potential therapeutic strategy for NSCLC patients with ROS1 fusion genes.
- Targeting ROS1 fusions offers a personalized medicine approach for a subset of NSCLC patients.
