Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1gene.[5][6]
Function
This proto-oncogene, highly expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor.[6]
ROS1 is a receptor tyrosine kinase (encoded by the gene ROS1) with structural similarity to the anaplastic lymphoma kinase (ALK) protein; it is encoded by the c-ros oncogene and was first identified in 1986.[7][8][9][10] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.[8] Nonetheless, as gene rearrangement events involving ROS1 have been described in lung and other cancers, and since such tumors have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has been increasing.[7][11] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.[12]
Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[13][14] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.[15] Since that discovery, multiple studies have demonstrated an incidence of approximately 1% in lung cancers, demonstrated oncogenicity, and showed that inhibition of tumor cells bearing ROS1 gene fusions by crizotinib or other ROS1tyrosine kinase inhibitors was effective in vitro.[16][17][18] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.[19][20] Preclinical and clinical work suggests multiple potential mechanisms of drug resistance in ROS1 + lung cancer, including kinase domain mutations in ROS1 and bypass signaling via RAS and EGFR.[21][22][23] Although the most preclinical and clinical studies of ROS1 gene fusions have been performed in lung cancer, ROS1 fusions have been detected in multiple other tumor histologies, including ovarian carcinoma, sarcoma, cholangiocarcinomas and others.[24] Crizotinib or other ROS1 inhibitors may be effective in other tumor histologies beyond lung cancer as demonstrated by a patient with an inflammatory myofibroblastic tumor harboring a ROS1 fusion with a dramatic response to crizotinib.[25]
Preclinical findings
From a large-scale survey of tyrosine kinase activity in non-small cell lung cancer (NSCLC), and identified more than 50 distinct tyrosine kinases and over 2500 downstream substrates, with the goal of identifying candidate oncogenes.[26] In a sampling of 96 tissue samples from NSCLC patients, approximately 30% displayed high levels of phosphotyrosine expression; further analysis was conducted to identify highly phosphorylated tyrosine kinases in NSCLC from a panel of 41 NSCLC cell lines, and 150 patient samples.[26] Among the top 20 receptor tyrosine kinases identified in this analysis, 15 were identified in both cell lines and tumors, and among these were both ALK and ROS1.[26] These initial findings paved the way for more expansive analyses of ROS1 kinase fusions in NSCLC and other cancers.
Fusion prevalence
In patients with NSCLC, approximately 2% are positive for a ROS1 gene rearrangement, and these rearrangements are mutually exclusive of ALK rearrangement.[27]ROS1 fusion-positive patients tend to be younger, with a median age of 49.8 years, and never-smokers, with a diagnosis of adenocarcinoma. There is a higher representation of Asian ethnicity and patients with Stage IV disease.[27]ROS1 rearrangements are estimated to be roughly half as common as ALK-rearranged NSCLCs. Similar to ALK-rearranged, ROS1-rearranged NSCLC have younger age of onset and a non-smoking history.[27] A benefit of a small-molecule ALK, ROS1 , and cMET inhibitor, crizotinib, was also shown in this patient group.
ROS1 expression was found in approximately 2% of NSCLC patients, and its expression was limited to those patients with ROS1 gene fusions.[11] Similar findings were reported in a separate analysis of 447 NSCLC samples, of which 1.2% were found to be positive for ROS1 rearrangement; this study also confirmed the activity of the ALK/ROS1 /cMET inhibitor crizotinib in ROS1 -positive tumors.[8]ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers.[28]
Table 1: Sampling of ROS1 Rearrangements Observed in NSCLC and Other Cancers. All of the kinase fusions retain the tyrosine kinase domain of ROS1 . List is not exhaustive. (Adapted from Stumpfova 2012).
CD74; cluster of differentiation 74, long/short isoforms; EZR; ezrin; FIG; fused in glioblastoma; SDC4; LRIG3; leucine-rich repeats and immunoglobulin-like domains 3; SDC; syndecan 4; SLC34A2; solute carrier family 34 (sodium phosphate), member 2; TPM3; tropomyosin 3
As a drug target
Several drugs target ROS1 fusions in cancer, with varying levels of success; most of the drugs to date have been tested only for ROS1-positive non-small cell lung carcinoma (NSCLC).[29] However, some clinical trials (like those for entrectinib, DS-6051b, and TPX-0005) accept patients with ROS1 cancer in any type of solid tumor.
Crizotinib is approved for treating metastatic ROS1-positive NSCLC in many countries. In clinical trials, crizotinib was shown to be effective for 70-80% of ROS1+ NSCLC patients, but it does not effectively treat the brain. Some patients have a response that lasts for years.[30] Crizotinib is available to patients with solid tumors other than NSCLC through clinical trials.[31][32]
Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 started in 2015 to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.[33]
Lorlatinib (also known as PF-06463922) was shown in an ongoing Phase 2 clinical trial to be effective in some ROS1+ NSCLC patients, and treats the cancer in the brain as well as the body. Lorlatinib has the potential to overcome certain resistance mutations that develop during treatment with crizotinib.[34]
Ceritinib demonstrates clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy. In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for some patients. Ceritinib is US FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer.[35][36]
TPX-0005 preclinical data suggests it is a potent inhibitor of ROS1+ cancer.[37] A Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements.[38]
DS-6051b preclinical data show it is active against ROS1-positive cancers.[34] It is an ongoing clinical trial.[39]
Cabozantinib preclinical data has shown the drug might overcome crizotinib resistance in ROS1+ cancer in early studies.[40] However, the required dosage makes the drug difficult to tolerate for many patients. Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx).
The ROS1ders
The ROS1ders [41] is a worldwide collaboration of ROS1+ cancer patients and caregivers with a goal of improving patient outcomes and accelerating research for any type of ROS1+ cancer. It is the first such collaboration focused on cancers driven by a single oncogene. Their website tracks targeted therapies, clinical trials, world experts and new developments for ROS1+ cancers.[42] Partners include patient-focused nonprofits, clinicians who treat ROS1+ patients, ROS1 researchers, pharmaceutical firms and biotech companies.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Galland F, Stefanova M, Lafage M, Birnbaum D (July 1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15----q23". Cytogenetics and Cell Genetics. 60 (2): 114–6. doi:10.1159/000133316. PMID1611909.
^Rabin M, Birnbaum D, Young D, Birchmeier C, Wigler M, Ruddle FH (July 1987). "Human ros1 and mas1 oncogenes located in regions of chromosome 6 associated with tumor-specific rearrangements". Oncogene Research. 1 (2): 169–78. PMID3329713.
^Clinical trial number NCT02465060 for "NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma" at ClinicalTrials.gov
^Clinical trial number NCT02693535 for "TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (TAPUR)" at ClinicalTrials.gov
^Clinical trial number NCT02568267 for "Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) (STARTRK-2)" at ClinicalTrials.gov
^Califano R, Greystoke A, Lal R, Thompson J, Popat S (2017). "Management of ceritinib therapy and adverse events in patients with ALK-rearranged non-small cell lung cancer". Lung Cancer (Amsterdam, Netherlands). 111: 51–58. doi:10.1016/j.lungcan.2017.06.004. hdl:10044/1/54441. PMID28838397.
^Clinical trial number NCT03093116 for "A Study of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)" at ClinicalTrials.gov
^Clinical trial number NCT02279433 for "A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b" at ClinicalTrials.gov
Satoh H, Yoshida MC, Matsushime H, Shibuya M, Sasaki M (August 1987). "Regional localization of the human c-ros-1 on 6q22 and flt on 13q12". Japanese Journal of Cancer Research. 78 (8): 772–5. PMID3115921.
Charest A, Lane K, McMahon K, Park J, Preisinger E, Conroy H, Housman D (May 2003). "Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21)". Genes, Chromosomes & Cancer. 37 (1): 58–71. doi:10.1002/gcc.10207. PMID12661006. S2CID39776967.
Girish V, Sachdeva N, Minz RW, Radotra B, Mathuria SN, Arora SK (July 2005). "Bcl2 and ROS1 expression in human meningiomas: an analysis with respect to histological subtype". Indian Journal of Pathology & Microbiology. 48 (3): 325–30. PMID16761743.
