ROS1

ROS proto-oncogene 1 , receptor tyrosine kinase
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ROS1 ; MCF3; ROS; c-ros-1
External IDs OMIM: 165020 MGI: 97999 HomoloGene: 2207 ChEMBL: 5568 GeneCards: ROS1 Gene
EC number 2.7.10.1
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 NP_035412
Location (UCSC) Chr 6:
117.29 – 117.43 Mb		 Chr 10:
52.05 – 52.2 Mb
PubMed search

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.[1][2]

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.[2]

Interactions

ROS1 (gene) has been shown to interact with PTPN6.[3]

Role in cancer

Gene rearrangements involving the ROS1 gene were first detected in glioblastoma tumors and cell lines.[4][5] In 2007 a ROS1 rearrangement was identified in a cell line derived from a lung adenocarcinoma patient.[6] 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.[7][8][9] Clinical data supports the use of crizotinib in lung cancer patients with ROS1 gene fusions.[10][11] 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.[12][13][14] 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.[15] 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.[16]

References

  1. ↑ 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.
  2. 1 2 "Entrez Gene: ROS1 v-ros UR2 sarcoma virus oncogene homolog 1 (avian)".
  3. ↑ Keilhack H, Müller M, Böhmer SA, Frank C, Weidner KM, Birchmeier W, Ligensa T, Berndt A, Kosmehl H, Günther B, Müller T, Birchmeier C, Böhmer FD (Jan 2001). "Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1". The Journal of Cell Biology 152 (2): 325–34. doi:10.1083/jcb.152.2.325. PMC 2199605. PMID 11266449.
  4. ↑ Rabin M, Birnbaum D, Young D, Birchmeier C, Wigler M, Ruddle FH (Jul 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.
  5. ↑ Birchmeier C, Sharma S, Wigler M (Dec 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.
  6. ↑ 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 (Dec 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.
  7. ↑ 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 (Mar 2012). "RET, ROS1 and ALK fusions in lung cancer". Nature Medicine 18 (3): 378–81. doi:10.1038/nm.2658. PMID 22327623.
  8. ↑ 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 (Mar 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. PMID 22215748.
  9. ↑ 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 (Sep 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. PMID 22919003.
  10. ↑ 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 (Nov 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.
  11. ↑ 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 (Mar 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.
  12. ↑ 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 (Jun 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.
  13. ↑ 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. PMID 24349229.
  14. ↑ Cargnelutti M, Corso S, Pergolizzi M, Mévellec L, Aisner DL, Dziadziuszko R, Varella-Garcia M, Comoglio PM, Doebele RC, Vialard J, Giordano S (Mar 2015). "Activation of RAS family members confers resistance to ROS1 targeting drugs". Oncotarget 6 (7): 5182–94. doi:10.18632/oncotarget.3311. PMID 25691052.
  15. ↑ Davies KD, Doebele RC (Aug 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.
  16. ↑ Lovly CM, Gupta A, Lipson D, Otto G, Brennan T, Chung CT, Borinstein SC, Ross JS, Stephens PJ, Miller VA, Coffin CM (Aug 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.

Further reading

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