Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT83NCEB)

• DOT Name: Ras-related protein R-Ras2 (RRAS2)
• Synonyms: EC 3.6.5.-; Ras-like protein TC21; Teratocarcinoma oncogene
• Gene Name: RRAS2
• Related Disease:
  Bone osteosarcoma
  Noonan syndrome
  Osteosarcoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Chronic myelomonocytic leukaemia
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Leukoplakia
  Lymphoma
  Megalencephaly
  Neoplasm
  Neoplasm of esophagus
  Noonan syndrome 12
  Oral cancer
  Skin cancer
  Squamous cell carcinoma
  Carcinoma
  Leiomyosarcoma
  Parkinson disease
  Ovarian cancer
• UniProt ID: RRAS2_HUMAN
• PDB ID: 2ERY
• EC Number: 3.6.5.-
• Pfam ID: PF00071
• Sequence:
  MAAAGWRDGSGQEKYRLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCVIDDR
  AARLDILDTAGQEEFGAMREQYMRTGEGFLLVFSVTDRGSFEEIYKFQRQILRVKDRDEF
  PMILIGNKADLDHQRQVTQEEGQQLARQLKVTYMEASAKIRMNVDQAFHELVRVIRKFQE
  QECPPSPEPTRKEKDKKGCHCVIF
• Function: GTP-binding protein with GTPase activity involved in the regulation of MAPK signaling pathway, thereby controlling multiple cellular processes. Involved in the regulation of MAPK signaling pathway. Regulation of craniofacial development.
• Tissue Specificity: Ubiquitously present in all tissues examined, with the highest levels in heart, placenta, and skeletal muscle. Moderate levels in lung and liver; low levels in brain, kidney, and pancreas.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  cAMP sig.ling pathway (hsa04024)
  Phospholipase D sig.ling pathway (hsa04072)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Cellular senescence (hsa04218)
  Apelin sig.ling pathway (hsa04371)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Regulation of actin cytoskeleton (hsa04810)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway: RND1 GTPase cycle (R-HSA-9696273)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[2]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Leukoplakia	DIST3QD3	Strong	Altered Expression	[3]
Lymphoma	DISN6V4S	Strong	Altered Expression	[8]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Noonan syndrome 12	DIS5W8Q8	Strong	Autosomal dominant	[10]
Oral cancer	DISLD42D	Strong	Biomarker	[3]
Skin cancer	DISTM18U	Strong	Altered Expression	[11]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	moderate	Altered Expression	[8]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[12]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[13]
Ovarian cancer	DISZJHAP	No Known	Unknown	[14]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Ras-related protein R-Ras2 (RRAS2) decreases the response to substance of Capecitabine.	[34]
Afimoxifene	DMFORDT	Phase 2	Ras-related protein R-Ras2 (RRAS2) affects the response to substance of Afimoxifene.	[35]

22 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ras-related protein R-Ras2 (RRAS2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-related protein R-Ras2 (RRAS2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein R-Ras2 (RRAS2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Ras-related protein R-Ras2 (RRAS2).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein R-Ras2 (RRAS2).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ras-related protein R-Ras2 (RRAS2).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras-related protein R-Ras2 (RRAS2).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras-related protein R-Ras2 (RRAS2).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related protein R-Ras2 (RRAS2).	[23]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ras-related protein R-Ras2 (RRAS2).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related protein R-Ras2 (RRAS2).	[24]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras-related protein R-Ras2 (RRAS2).	[25]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Ras-related protein R-Ras2 (RRAS2).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Ras-related protein R-Ras2 (RRAS2).	[26]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Ras-related protein R-Ras2 (RRAS2).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ras-related protein R-Ras2 (RRAS2).	[23]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Ras-related protein R-Ras2 (RRAS2).	[28]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Ras-related protein R-Ras2 (RRAS2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ras-related protein R-Ras2 (RRAS2).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ras-related protein R-Ras2 (RRAS2).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ras-related protein R-Ras2 (RRAS2).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein R-Ras2 (RRAS2).	[33]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Clinical significance of TC21 overexpression in oral cancer.J Oral Pathol Med. 2010 Jul;39(6):477-85. doi: 10.1111/j.1600-0714.2009.00854.x. Epub 2009 Dec 16.
• [4] A polymorphism in the TC21 promoter associates with an unfavorable tamoxifen treatment outcome in breast cancer.Cancer Res. 2008 Dec 1;68(23):9799-808. doi: 10.1158/0008-5472.CAN-08-0247.
• [5] siRNA-mediated downregulation of TC21 sensitizes esophageal cancer cells to cisplatin.World J Gastroenterol. 2012 Aug 21;18(31):4127-35. doi: 10.3748/wjg.v18.i31.4127.
• [6] The genomic landscape of juvenile myelomonocytic leukemia.Nat Genet. 2015 Nov;47(11):1326-1333. doi: 10.1038/ng.3400. Epub 2015 Oct 12.
• [7] Frequent amplification of CENPF, GMNN and CDK13 genes in hepatocellular carcinomas.PLoS One. 2012;7(8):e43223. doi: 10.1371/journal.pone.0043223. Epub 2012 Aug 13.
• [8] R-RAS2 overexpression in tumors of the human central nervous system.Mol Cancer. 2013 Oct 23;12(1):127. doi: 10.1186/1476-4598-12-127.
• [9] Germline-Activating RRAS2 Mutations Cause Noonan Syndrome. Am J Hum Genet. 2019 Jun 6;104(6):1233-1240. doi: 10.1016/j.ajhg.2019.04.014. Epub 2019 May 23.
• [10] Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome. Am J Hum Genet. 2019 Jun 6;104(6):1223-1232. doi: 10.1016/j.ajhg.2019.04.013. Epub 2019 May 23.
• [11] UVA and UVB irradiation differentially regulate microRNA expression in human primary keratinocytes.PLoS One. 2013 Dec 31;8(12):e83392. doi: 10.1371/journal.pone.0083392. eCollection 2013.
• [12] Ras-related TC21 is activated by mutation in a breast cancer cell line, but infrequently in breast carcinomas in vivo.Br J Cancer. 1998 Aug;78(3):296-300. doi: 10.1038/bjc.1998.490.
• [13] SNPs in axon guidance pathway genes and susceptibility for Parkinson's disease in the Korean population.J Hum Genet. 2011 Feb;56(2):125-9. doi: 10.1038/jhg.2010.130. Epub 2010 Nov 18.
• [14] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [22] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [23] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [24] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [25] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
• [28] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [29] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [30] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [31] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [32] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [33] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [34] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [35] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.