ROS1

ROS1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3ZBF, 4UXL
Identifiers
Aliases	ROS1, MCF3, ROS, c-ros-1, ROS proto-oncogene 1, receptor tyrosine kinase
External IDs	MGI: 97999 HomoloGene: 2207 GeneCards: ROS1
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • kinase activity • protein binding • transmembrane receptor protein tyrosine kinase activity • protein tyrosine kinase activity • protein phosphatase binding • ATP binding Cellular component • integral component of membrane • membrane • plasma membrane • cell surface • perinuclear region of cytoplasm Biological process • cell differentiation • regulation of TOR signaling • signal transduction by protein phosphorylation • phosphorylation • transmembrane receptor protein tyrosine kinase signaling pathway • regulation of phosphate transport • negative regulation of gene expression • protein phosphorylation • cell growth • spermatogenesis • regulation of ERK1 and ERK2 cascade • peptidyl-tyrosine autophosphorylation • cell proliferation • columnar/cuboidal epithelial cell development Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6098	19886
Ensembl	ENSG00000047936	ENSMUSG00000019893
UniProt	P08922	Q78DX7
RefSeq (mRNA)	NM_002944	NM_011282
RefSeq (protein)	NP_002935.2	NP_035412.2
Location (UCSC)	Chr 6: 117.29 – 117.43 Mb	Chr 10: 52.05 – 52.2 Mb
PubMed search	[1]	[2]
Wikidata

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Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.^[3][4]

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.^[4]

Role in cancer

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.^[5][6][7][8] The exact role of the ROS1 protein in normal development, as well as its normal physiologic ligand, have not been defined.^[6] 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.^[5][9] Recently, the small molecule tyrosine kinase inhibitor, crizotinib, was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1 -positive.^[10]

Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.^[11][12] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.^[13] 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 ROS1 tyrosine kinase inhibitors was effective in vitro.^[14][15][16] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.^[17][18] 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.^[19][20][21] 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.^[22] 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.^[23]

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.^[24] 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.^[24] 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 ^[24] 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.^[25] 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.^[25] 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.^[25] 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.^[9] 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.^[6] ROS1 fusions were also identified in approximately 2% of adenocarcinomas and 1% of glioblastoma samples in an assessment of kinase fusions across different cancers.^[26]

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).

Cancer Type	ROS1 Fusion Gene
NSCLC	FIG - ROS1*; SLC34A2 - ROS1*; CD74 - ROS1*; SDC - ROS1*; EZR - ROS1; LRIG3 - ROS1; TPM3 - ROS1
Gastric	SLC34A2 - ROS1*
Colorectal	SLC34A2 - ROS1*
Spitzoid melanoma	TPM3 - ROS1
Cholangiosarcoma	FIG - ROS1*
Glioblastoma	FIG - ROS1*
Ovarian	FIG - ROS1*
Angiosarcoma	CEP85L-ROS1

* Multiple variant isoforms observed

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

• 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 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.
• Lorlatinib
• Ceritnib
• Merestinib

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. 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. PMID 1611909.
4. "Entrez Gene: ROS1 v-ros UR2 sarcoma virus oncogene homolog 1 (avian)".
5. Berge EM, Doebele RC (February 2014). "Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor". Seminars in Oncology. 41 (1): 110–25. doi:10.1053/j.seminoncol.2013.12.006. PMC 4159759. PMID 24565585.
6. Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Roncalli M, Alloisio M, Santoro A, Camidge DR, Varella-Garcia M, Doebele RC (September 2012). "Identifying and targeting ROS1 gene fusions in non-small cell lung cancer". Clinical Cancer Research. 18 (17): 4570–9. doi:10.1158/1078-0432.CCR-12-0550. PMC 3703205. PMID 22919003.
7. Matsushime H, Wang LH, Shibuya M (August 1986). "Human c-ros-1 gene homologous to the v-ros sequence of UR2 sarcoma virus encodes for a transmembrane receptorlike molecule". Molecular and Cellular Biology. 6 (8): 3000–4. PMC 367872. PMID 3023956.
8. Birchmeier C, Birnbaum D, Waitches G, Fasano O, Wigler M (September 1986). "Characterization of an activated human ros gene". Molecular and Cellular Biology. 6 (9): 3109–16. PMC 367045. PMID 3785223.
9. Rimkunas VM, Crosby KE, Li D, Hu Y, Kelly ME, Gu TL, Mack JS, Silver MR, Zhou X, Haack H (August 2012). "Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion". Clinical Cancer Research. 18 (16): 4449–57. doi:10.1158/1078-0432.CCR-11-3351. PMID 22661537.
10. Berge EM, Doebele RC (February 2014). "Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor". Seminars in Oncology. 41 (1): 110–25. doi:10.1053/j.seminoncol.2013.12.006. PMC 4159759. PMID 24565585.
11. 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. PMID 3329713.
12. Birchmeier C, Sharma S, Wigler M (December 1987). "Expression and rearrangement of the ROS1 gene in human glioblastoma cells". Proceedings of the National Academy of Sciences of the United States of America. 84 (24): 9270–4. doi:10.1073/pnas.84.24.9270. PMC 299735. PMID 2827175.
13. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (December 2007). "Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer". Cell. 131 (6): 1190–203. doi:10.1016/j.cell.2007.11.025. PMID 18083107.
14. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y (March 2012). "RET, ROS1 and ALK fusions in lung cancer". Nature Medicine. 18 (3): 378–81. doi:10.1038/nm.2658. PMID 22327623.
15. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ (March 2012). "ROS1 rearrangements define a unique molecular class of lung cancers". Journal of Clinical Oncology. 30 (8): 863–70. doi:10.1200/JCO.2011.35.6345. PMC 3295572. PMID 22215748.
16. Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM, Terracciano LM, Cappuzzo F, Incarbone M, Roncalli M, Alloisio M, Santoro A, Camidge DR, Varella-Garcia M, Doebele RC (September 2012). "Identifying and targeting ROS1 gene fusions in non-small cell lung cancer". Clinical Cancer Research. 18 (17): 4570–9. doi:10.1158/1078-0432.CCR-12-0550. PMC 3703205. PMID 22919003.
17. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ (November 2014). "Crizotinib in ROS1-rearranged non-small-cell lung cancer". The New England Journal of Medicine. 371 (21): 1963–71. doi:10.1056/NEJMoa1406766. PMID 25264305.
18. Mazières J, Zalcman G, Crinò L, Biondani P, Barlesi F, Filleron T, Dingemans AM, Léna H, Monnet I, Rothschild SI, Cappuzzo F, Besse B, Thiberville L, Rouvière D, Dziadziuszko R, Smit EF, Wolf J, Spirig C, Pecuchet N, Leenders F, Heuckmann JM, Diebold J, Milia JD, Thomas RK, Gautschi O (March 2015). "Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort". Journal of Clinical Oncology. 33 (9): 992–9. doi:10.1200/JCO.2014.58.3302. PMID 25667280.
19. Awad MM, Katayama R, McTigue M, Liu W, Deng YL, Brooun A, Friboulet L, Huang D, Falk MD, Timofeevski S, Wilner KD, Lockerman EL, Khan TM, Mahmood S, Gainor JF, Digumarthy SR, Stone JR, Mino-Kenudson M, Christensen JG, Iafrate AJ, Engelman JA, Shaw AT (June 2013). "Acquired resistance to crizotinib from a mutation in CD74-ROS1". The New England Journal of Medicine. 368 (25): 2395–401. doi:10.1056/NEJMoa1215530. PMID 23724914.
20. Davies KD, Mahale S, Astling DP, Aisner DL, Le AT, Hinz TK, Vaishnavi A, Bunn PA, Heasley LE, Tan AC, Camidge DR, Varella-Garcia M, Doebele RC (2013). "Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer". PloS One. 8 (12): e82236. doi:10.1371/journal.pone.0082236. PMC 3862576. PMID 24349229.
21. Cargnelutti M, Corso S, Pergolizzi M, Mévellec L, Aisner DL, Dziadziuszko R, Varella-Garcia M, Comoglio PM, Doebele RC, Vialard J, Giordano S (March 2015). "Activation of RAS family members confers resistance to ROS1 targeting drugs". Oncotarget. 6 (7): 5182–94. doi:10.18632/oncotarget.3311. PMID 25691052.
22. Davies KD, Doebele RC (August 2013). "Molecular pathways: ROS1 fusion proteins in cancer". Clinical Cancer Research. 19 (15): 4040–5. doi:10.1158/1078-0432.CCR-12-2851. PMID 23719267.
23. Lovly CM, Gupta A, Lipson D, Otto G, Brennan T, Chung CT, Borinstein SC, Ross JS, Stephens PJ, Miller VA, Coffin CM (August 2014). "Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions". Cancer Discovery. 4 (8): 889–95. doi:10.1158/2159-8290.CD-14-0377. PMID 24875859.
24. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (December 2007). "Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer". Cell. 131 (6): 1190–203. doi:10.1016/j.cell.2007.11.025. PMID 18083107.
25. Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, Massion PP, Siwak-Tapp C, Gonzalez A, Fang R, Mark EJ, Batten JM, Chen H, Wilner KD, Kwak EL, Clark JW, Carbone DP, Ji H, Engelman JA, Mino-Kenudson M, Pao W, Iafrate AJ (March 2012). "ROS1 rearrangements define a unique molecular class of lung cancers". Journal of Clinical Oncology. 30 (8): 863–70. doi:10.1200/JCO.2011.35.6345. PMC 3295572. PMID 22215748.
26. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C (2014-01-01). "The landscape of kinase fusions in cancer". Nature Communications. 5: 4846. doi:10.1038/ncomms5846. PMC 4175590. PMID 25204415.

Further reading

• Birchmeier C, O'Neill K, Riggs M, Wigler M (June 1990). "Characterization of ROS1 cDNA from a human glioblastoma cell line". Proceedings of the National Academy of Sciences of the United States of America. 87 (12): 4799–803. doi:10.1073/pnas.87.12.4799. PMC 54205. PMID 2352949.
• Sharma S, Birchmeier C, Nikawa J, O'Neill K, Rodgers L, Wigler M (1990). "Characterization of the ros1-gene products expressed in human glioblastoma cell lines". Oncogene Research. 5 (2): 91–100. PMID 2691958.
• Matsushime H, Wang LH, Shibuya M (August 1986). "Human c-ros-1 gene homologous to the v-ros sequence of UR2 sarcoma virus encodes for a transmembrane receptorlike molecule". Molecular and Cellular Biology. 6 (8): 3000–4. PMC 367872. PMID 3023956.
• 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. PMID 3115921.
• Birchmeier C, Birnbaum D, Waitches G, Fasano O, Wigler M (September 1986). "Characterization of an activated human ros gene". Molecular and Cellular Biology. 6 (9): 3109–16. PMC 367045. PMID 3785223.
• Sonnenberg-Riethmacher E, Walter B, Riethmacher D, Gödecke S, Birchmeier C (May 1996). "The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis". Genes & Development. 10 (10): 1184–93. doi:10.1101/gad.10.10.1184. PMID 8675006.
• Zeng L, Sachdev P, Yan L, Chan JL, Trenkle T, McClelland M, Welsh J, Wang LH (December 2000). "Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation". Molecular and Cellular Biology. 20 (24): 9212–24. doi:10.1128/MCB.20.24.9212-9224.2000. PMC 102179. PMID 11094073.
• Charest A, Kheifets V, Park J, Lane K, McMahon K, Nutt CL, Housman D (February 2003). "Oncogenic targeting of an activated tyrosine kinase to the Golgi apparatus in a glioblastoma". Proceedings of the National Academy of Sciences of the United States of America. 100 (3): 916–21. doi:10.1073/pnas.242741799. PMC 298701. PMID 12538861.
• 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. PMID 12661006.
• Légaré C, Sullivan R (September 2004). "Expression and localization of c-ros oncogene along the human excurrent duct". Molecular Human Reproduction. 10 (9): 697–703. doi:10.1093/molehr/gah087. PMID 15235104.
• Biskup C, Böhmer A, Pusch R, Kelbauskas L, Gorshokov A, Majoul I, Lindenau J, Benndorf K, Böhmer FD (October 2004). "Visualization of SHP-1-target interaction". Journal of Cell Science. 117 (Pt 21): 5165–78. doi:10.1242/jcs.01397. PMID 15456853.
• 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. PMID 16761743.