ROS1
ROS proto-oncogene 1 (ROS1)
ROS1 Biology
First identified in 1981, the ROS1 gene is located on chromosome 6 (6q22) and encodes a tyrosine kinase receptor protein involved in cellular growth and differentiation.1-3 The ROS1 protein is expressed in epithelial cells of various organs, including the lungs, heart, and kidneys.4,5 Upon activation, ROS1 triggers downstream signaling in cells, leading to the activation of pathways such as STAT3, PI3 kinase, and the RAS/RAF/MAPK pathway through the phosphorylation of RAS. In human malignancies, downstream effects of ROS1 are similar to those exerted by oncogenic activation of ALK or EGFR. ROS1 rearrangements in non–small cell lung cancer (NSCLC) were first identified in 2007 and have been reported to occur at a frequency ranging from 0.9% to 2%.1,2 Subsequently, multiple ROS1 fusion partners have been discovered, with CD47 being the most common, followed by SLC34A2, CCDC6, and GOPC.3 ROS1-positive NSCLCs, more common in young individuals, women, and nonsmokers, typically present as lepidic, acinar, or solid adenocarcinomas, often expressing transcription termination factor 1 (TTF1).6-12 They are usually diagnosed at advanced stages and appear to be associated with a higher frequency of brain metastases. Although less common, ROS1 rearrangements can also occur in other histological subtypes such as squamous-cell, pleomorphic, or large-cell carcinomas, and in patients with various demographics, therefore, these features should not restrict testing for patients.
ROS1 Testing
The National Comprehensive Cancer Network (NCCN) NSCLC Panel recommends ROS1 testing in patients with metastatic nonsquamous NSCLC or NSCLC not otherwise specified (NOS) based on efficacy data demonstrated with crizotinib, ceritinib, and entrectinib in patients with ROS1 rearrangements.13 Because ROS1 rearrangements have also been observed in metastatic squamous cell NSCLC, albeit a lower rate than nonsquamous NSCLC, ROS1 testing may also be considered for these patients.14,25 Several methods are available to detect ROS1 rearrangements, such as next generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and polymerase chain reaction (PCR) assays.16 FISH is considered the "gold standard" and was required for crizotinib registration trials. Discordance between IHC and FISH is possible, in which cases it is recommended to conduct NGS-based testing, although DNA-based NGS may underdetect ROS1 fusions.17 Therefore, RNA-based NGS may be considered for fusion assessment.
ROS1 Targeted Therapy
The presence of a ROS1 rearrangement is associated with a response to oral ROS1 tyrosine kinase inhibitors (TKIs). The US Food & Drug Administration (FDA) has approved 3 oral medications for treating ROS1-positive locally advanced or metastatic NSCLC. The first of these, crizotinib, is a TKI that targets ALK and ROS1.18 Although initially approved for ALK-positive NSCLC in 2011, crizoltinib’s approval was extended in 2016 to include NSCLC tumors with ROS1 alterations, marking it as the first targeted therapy for ROS1-positive NSCLC.19 Entrectinib, a TKI targeting tropomyosin receptor tyrosine kinases (TRKs) and ROS1, received expanded approval for ROS1-positive NSCLC in 2019.20,21 Most recently in 2023, repotrectinib, another TKI specific for ROS1 and TRKs, received approval for patients with ROS1-positive NSCLC who have previously undergone treatment with a ROS1 TKI, in addition to patients who are TKI naïve.22
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References
1. Balduzzi PC, Notter MF, Morgan HR, Shibuya M. Some biological properties of two new avian sarcoma viruses. J Virol. 1981;40(1):268-75.
2. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131(6):1190-203.
3. Charest A, Wilker EW, McLaughlin ME, et al. ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glio-blastoma in mice. Cancer Res. 2006;66:7473-7481.
4. Acquaviva J, Wong R, Charest A. The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta. 2009;1795(1):37-52.
5. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist.2013;18(7):865-75.
6. Zhang Q, Wu C, Ding W, et al. Prevalence of ROS1 fusion in Chinese patients with non-small cell lung cancer. Thorac Cancer. 2018;10:47-53.
7. Bergethon K, Shaw AT, Ou S-HI, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 2012;30:863-870.
8. Fu S, Liang Y, Lin Y-B, et al. The frequency and clinical implication of ROS1 and RET rearrangements in resected stage IIIA-N2 non-small cell lung cancer patients. PLoS ONE. 2015;10:e0124354.
9. Zhu Q, Zhan P, Zhang X, Lv T, Song Y. Clinicopathologic characteristics of patients with ROS1 fusion gene in non-small cell lung cancer: A meta-analysis. Transl. Lung Cancer Res. 2015;4:300-309.
10. Patil T, Smith DE, Bunn PA, et al. The incidence of brain metastases in stage IV ROS1-rearranged non–small cell lung cancer and rate of central nervous system progression on crizotinib. J. Thorac. Oncol. 2018;13:1717-1726.
11. Park S, Ahn B-C, Lim SW, et al. Characteristics and outcome of ROS1-positive non–small cell lung cancer patients in routine clinical practice. J. Thorac. Oncol. 2018;13:1373-1382.
12. Warth A, Muley T, Dienemann H, et al. ROS1expression and translocations in non-small-cell lung cancer: clinicopathological analysis of 1478 cases. Histopathology 2014;65:187-194.
13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 2.2024. Accessed March 6, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
14. Sands JM, Nguyen T, Shivdasani P, et al. Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas. Lung Cancer. 2020;140:35-41.
15. Lam VK, Tran HT, Banks KC, et al. Targeted tissue and cell-free tumor DNA sequencing of advanced lung squamous-cell carcinoma reveals clinically significant prevalence of actionable alterations. Clin Lung Cancer. 2019;20:30-36 e33.
16. Almquist D, Ernani V. The road less traveled: a guide to metastatic ros1-rearranged non-small-cell lung cancer. JCO Oncol Pract. 2021;17(1):7-14.
17. Gendarme S, Bylicki O, Chouaid C, Guisier F. ROS-1 fusions in non-small-cell lung cancer: evidence to date. Curr Oncol. 2022;29(2):641-658.
18. XALKORI (crizotinib) [package insert]. New York, NY, USA: Pfizer Labs; 19/2023.
19. FDA.gov. FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Updated March 11, 2016. Accessed March 6, 2024. https://www.fda.gov/news-events/press-announcements/fda-expands-use-xalkori-treat-rare-form-advanced-non-small-cell-lung-cancer
20. ROZLYTREK (entrectinib) [package insert]. San Francisco, CA, USA: Genentech USA, Inc.; 01/2024.
21. FDA.gov. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Updated August 16, 2019. Accessed March 6, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc
22. AUGTYRO (repotrectinib) [package insert]. Princeton, NJ, USA: Bristol Myers Squibb Company; 11/2023.
Additional Reading
Drilon, A., Jenkins, C., Iyer, S. et al. ROS1-dependent cancers — biology, diagnostics and therapeutics. Nat Rev Clin Oncol 18, 35–55 (2021).
Kerr K. ROS1 in lung Cancer: ESMO biomarker fact sheet. Updated on April 19, 2016. Accessed on March 6, 2024. https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/ros1-in-lung-cancer
Marinelli D, Siringo M, Metro G, Ricciuti B, Gelibter AJ. Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease. Drugs Context. 2022;11:2022-3-1.
Gendarme S, Bylicki O, Chouaid C, Guisier F. ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date. Curr Oncol. 2022;29(2):641-658
