ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers
Open accessAbstract
Purpose: Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non–small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Patients and Methods: Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. Results: Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. Conclusion: ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.
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ROS1 gene fusions are oncogenic molecular alterations that drive persistent downstream signaling and dysregulated cell differentiation, proliferation, and survival.
“Proto-oncogene tyrosine-protein kinase 1 (ROS1) gene fusions, first reported in 2007,1,2 are oncogenic molecular alterations resulting in constitutive activation of the ROS1 kinase domain and drive persistent downstream signaling and dysregulated cell differentiation, proliferation, and survival.”
From Taletrectinib in <i>ROS1</i> + Non–Small Cell Lung Cancer: TRUST (2025) · cites this paper as [2]
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- Authors
- Bergethon, K., Shaw, A. T., Ignatius Ou, S.-H., Katayama, R., Lovly, C. M., McDonald, N. T., Massion, P. P., Siwak-Tapp, C., Gonzalez, A., Fang, R., Mark, E. J., Batten, J. M., Chen, H., Wilner, K. D., Kwak, E. L., Clark, J. W., Carbone, D. P., Ji, H., Engelman, J. A., Mino-Kenudson, M., Pao, W., & Iafrate, A. J.
- Affiliations
- Author affiliations appear at the end of this article.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2012-03-10
- Volume
- 30
- Issue
- 8
- Pages
- 863-870
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3295572
- OpenAlex
- W2130488043
- Cited by
- 1,555
- References
- 23
- Citations by year
- 2026: 34 · 2025: 47 · 2024: 61 · 2023: 74 · 2022: 92 · 2021: 98 · 2020: 132 · 2019: 114 · 2018: 133 · 2017: 108 · 2016: 127 · 2015: 149 · 2014: 165 · 2013: 143 · 2012: 74
- FWCI
- 137.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- AstraZeneca
- American Society of Clinical Oncology
- Ariad Pharmaceuticals
- National Institutes of Health
- National Cancer Institute (R21CA161590)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- ROS1 rearrangement, non-small cell lung cancer, ALK rearrangement, crizotinib, tyrosine kinase inhibitors, CD74-ROS1 fusion, molecular subtypes, never smokers, adenocarcinoma, overall survival, targeted therapy
- MeSH terms
- Crizotinib, Anaplastic Lymphoma Kinase, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Drug Screening Assays, Antitumor, Female, Humans, Lung Neoplasms, Male, Middle Aged, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Pyrazoles, Pyridines, Retrospective Studies, Gene Rearrangement, Treatment Outcome, In Situ Hybridization, Fluorescence, Receptor Protein-Tyrosine Kinases, Protein Kinase Inhibitors
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