Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9VMY7B)

• DOT Name: Retinoblastoma tumor suppressor (RB1)
• Gene Name: RB1
• Related Disease:
  Acute kidney injury
  Adrenocortical carcinoma
  Sarcoma
  Acute lymphocytic leukaemia
  Adrenal gland cancer
  Adrenal gland neoplasm
  Carcinoma
  Endometrial carcinoma
  Fetal growth restriction
  Gastrointestinal stromal tumour
  Glioblastoma multiforme
  Hypotrichosis 8
  Malignant neoplasm
  Melanoma
  Non-small-cell lung cancer
  Pancreatic tumour
  Pituitary tumor
  Plasma cell myeloma
  Sezary syndrome
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Stevens-Johnson syndrome
  Toxic epidermal necrolysis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Brain ischaemia
  Breast neoplasm
  Osteosarcoma
  Prostate cancer
  Bladder cancer
  Hereditary neoplastic syndrome
  Bladder transitional cell carcinoma
  Bone osteosarcoma
  Childhood acute lymphoblastic leukemia
  Glioma
  Leukemia
  Lung neoplasm
  Lymphoma
  Prostate neoplasm
  Small-cell lung cancer
  Undifferentiated carcinoma
• UniProt ID: Q5J3Q9_FUNHE
• Pfam ID: PF11934 ; PF01858 ; PF01857 ; PF08934
• Sequence:
  MPPKKRHSGLTGSREPKPDGDSASSPDKQESPELSEEKHRDKNAEFVSLCKSLHVSDLLC
  DRAWLLWRTVQESMDKAPGSQERLWAACLFVTVTDMDVGCFTVTQVLKAVRLNLKQFLDV
  VRQLDVNLDTITTKVNSRLTRLEKKYDVMLALYQRFEKTCKSIFVLTPDGRERETMRTCW
  TMFLLAKGRALQMEDDLVISFQLLLCTLELIIKRCSPDQLQPLYQSAVTKVQSPPTRTSR
  RSQSKAKSRPAEPEVDARLLETLCKDNECNIEEVKNVYNTSFLAFLDSMDLSRAAGVPQA
  KDINRLYEEHYLKSRDVDGRLFFDGDESVLPPKVQISQVERTPKKNQPDEDGPMIPPPTP
  IRAAMTSIQMLRGDLPSNGDRPSATLATYFKNCTVDPTQDVQKRLETLGQAFSQKFGEAA
  GPHCVVYGQQRFGLAVRLYYKVMEAMLKSEEKRLSVQNFSKLLNDATFHTSLLACSLEVV
  MATYEESSFKNGGGDQTGTNLCFPWILNVLNLSAFDFYKVIESFIKAEPTLSKDIIKHLE
  TCENLIMERIAWRTGSPLFELLQQEHASAAAEPVETTASFSQPLQHNHTAADLYLSPVRQ
  GLRVLPSDSPATPPQQPTASQSSAQAPCQAPRQPKSNSLSLFYKKLYRLAYTRLKTLCSY
  LLSSHPELEPIIWTLFQYTLQHEYELMRDRHLDQLMMSAMYAICKVKSVDLRFKSIVSAY
  KNMANTNQETFKNVLITEGHYDSIIVFYNQVFMQKLKTNILQHASTKPPPPSPIPQMPRS
  PYKFPNSPLRVPGSNNVYISPLKNSRMSPGIMTPRSRMLVSIGESFGLSNRFQKINQMVN
  SSERSHKRTMDSGSTLKPLKRLRFDMDGQDEADGSKPGGDSTLIQKLTEMSSTWNRIHEQ
  KMKEDPDTREEPQ

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute kidney injury	DISXZG0T	Definitive	Biomarker	[1]
Adrenocortical carcinoma	DISZF4HX	Definitive	Biomarker	[2]
Sarcoma	DISZDG3U	Definitive	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
Adrenal gland cancer	DISNFZKJ	Strong	Biomarker	[5]
Adrenal gland neoplasm	DISFK7RF	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Fetal growth restriction	DIS5WEJ5	Strong	Altered Expression	[8]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[10]
Hypotrichosis 8	DIS2FX7S	Strong	Genetic Variation	[11]
Malignant neoplasm	DISS6SNG	Strong	Biomarker	[12]
Melanoma	DIS1RRCY	Strong	Posttranslational Modification	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[14]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[15]
Pituitary tumor	DISN67JD	Strong	Posttranslational Modification	[16]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[17]
Sezary syndrome	DISFMTC7	Strong	Biomarker	[18]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[19]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[20]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[21]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[22]
Brain ischaemia	DIS9Q4RT	moderate	Biomarker	[23]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[24]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[25]
Prostate cancer	DISF190Y	moderate	Biomarker	[26]
Bladder cancer	DISUHNM0	Disputed	Biomarker	[3]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[27]
Bladder transitional cell carcinoma	DISNL46A	Limited	Genetic Variation	[28]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[25]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Biomarker	[4]
Glioma	DIS5RPEH	Limited	Biomarker	[29]
Leukemia	DISNAKFL	Limited	Biomarker	[30]
Lung neoplasm	DISVARNB	Limited	Biomarker	[31]
Lymphoma	DISN6V4S	Limited	Altered Expression	[32]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[26]
Small-cell lung cancer	DISK3LZD	Limited	Altered Expression	[33]
Undifferentiated carcinoma	DISIAZST	Limited	Biomarker	[34]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Retinoblastoma tumor suppressor (RB1) increases the Cytogenetic abnormality ADR of Etoposide.	[35]

References

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• [2] Integrated genomic characterization of adrenocortical carcinoma.Nat Genet. 2014 Jun;46(6):607-12. doi: 10.1038/ng.2953. Epub 2014 Apr 20.
• [3] Detection of LOH of the RB1 gene in bladder cancers by PCR-RFLP.Urol Int. 2002;68(3):189-92. doi: 10.1159/000048448.
• [4] Prognostic significance of copy number alterations detected by multi-link probe amplification of multiple genes in adult acute lymphoblastic leukemia.Oncol Lett. 2018 Apr;15(4):5359-5367. doi: 10.3892/ol.2018.7985. Epub 2018 Feb 7.
• [5] Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.Nat Genet. 2014 Jun;46(6):613-7. doi: 10.1038/ng.2956. Epub 2014 Apr 20.
• [6] Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma.Mod Pathol. 2015 Aug;28(8):1023-32. doi: 10.1038/modpathol.2015.60. Epub 2015 May 29.
• [7] Progesterone receptor-B induction of BIRC3 protects endometrial cancer cells from AP1-59-mediated apoptosis.Horm Cancer. 2011 Jun;2(3):170-81. doi: 10.1007/s12672-011-0065-7.
• [8] Expression of Homeobox Gene HLX and its Downstream Target Genes are Altered in Placentae From Discordant Twin Pregnancies.Twin Res Hum Genet. 2018 Feb;21(1):42-50. doi: 10.1017/thg.2017.66. Epub 2017 Dec 7.
• [9] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [10] Detection of Aberrant DNA Methylation Patterns in the RB1 Gene.Methods Mol Biol. 2018;1726:35-47. doi: 10.1007/978-1-4939-7565-5_5.
• [11] In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis.PLoS One. 2014 Aug 13;9(8):e104756. doi: 10.1371/journal.pone.0104756. eCollection 2014.
• [12] Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy.Cell Cycle. 2017 Feb;16(3):251-258. doi: 10.1080/15384101.2016.1175798. Epub 2016 Apr 28.
• [13] SUV39H1/DNMT3A-dependent methylation of the RB1 promoter stimulates PIN1 expression and melanoma development.FASEB J. 2018 Oct;32(10):5647-5660. doi: 10.1096/fj.201700645RRRRR. Epub 2018 May 11.
• [14] Nicotine upregulates FGFR3 and RB1 expression and promotes non-small cell lung cancer cell proliferation and epithelial-to-mesenchymal transition via downregulation of miR-99b and miR-192.Biomed Pharmacother. 2018 May;101:656-662. doi: 10.1016/j.biopha.2018.02.113. Epub 2018 Mar 22.
• [15] Deletion of Rb accelerates pancreatic carcinogenesis by oncogenic Kras and impairs senescence in premalignant lesions.Gastroenterology. 2011 Sep;141(3):1091-101. doi: 10.1053/j.gastro.2011.05.041. Epub 2011 May 27.
• [16] Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas.J Neurooncol. 2007 Jun;83(2):153-62. doi: 10.1007/s11060-006-9316-9. Epub 2007 Jan 11.
• [17] Plasma cell labeling index correlates with deletion of 13q14 in multiple myeloma.Leuk Lymphoma. 2011 Feb;52(2):260-4. doi: 10.3109/10428194.2010.538775. Epub 2010 Dec 6.
• [18] The mutational landscape of cutaneous T cell lymphoma and Szary syndrome.Nat Genet. 2015 Dec;47(12):1465-70. doi: 10.1038/ng.3442. Epub 2015 Nov 9.
• [19] The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia.Clin Cancer Res. 2011 Nov 1;17(21):6778-90. doi: 10.1158/1078-0432.CCR-11-0785. Epub 2011 Sep 2.
• [20] Abrogation of the p16-retinoblastoma-cyclin D1 pathway in head and neck squamous cell carcinomas.Oncol Rep. 2007 Jul;18(1):267-72.
• [21] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [22] Methylation patterns of Rb1 and Casp-8 promoters and their impact on their expression in bladder cancer.Cancer Invest. 2009 Jan;27(1):70-80. doi: 10.1080/07357900802172085.
• [23] Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase.Endocrinology. 2008 Jan;149(1):367-79. doi: 10.1210/en.2007-0899. Epub 2007 Sep 27.
• [24] Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial.Breast Cancer Res Treat. 2015 Jun;151(2):309-18. doi: 10.1007/s10549-015-3397-0. Epub 2015 Apr 28.
• [25] Prognostic implications of RB1 tumour suppressor gene alterations in the clinical outcome of human osteosarcoma: a meta-analysis.Eur J Cancer Care (Engl). 2017 Jan;26(1). doi: 10.1111/ecc.12401. Epub 2015 Oct 27.
• [26] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [27] Mutational analysis of the RB1 gene and the inheritance patterns of retinoblastoma in Jordan.Fam Cancer. 2018 Apr;17(2):261-268. doi: 10.1007/s10689-017-0027-5.
• [28] Expression of bcl-2 and bcl-X in bladder cancer.J Urol. 1998 Apr;159(4):1348-53.
• [29] Insilico analysis identified miRNAbased therapeutic agents against glioblastoma multiforme.Oncol Rep. 2019 Apr;41(4):2194-2208. doi: 10.3892/or.2019.7022. Epub 2019 Feb 19.
• [30] DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells.Int J Cancer. 2007 Aug 15;121(4):706-13. doi: 10.1002/ijc.22634.
• [31] Retinoblastoma deficiency increases chemosensitivity in lung cancer.Cancer Res. 2007 Sep 1;67(17):8264-73. doi: 10.1158/0008-5472.CAN-06-4753.
• [32] Telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway in pyothorax-associated lymphoma.Cancer Sci. 2007 Jul;98(7):978-84. doi: 10.1111/j.1349-7006.2007.00482.x. Epub 2007 Apr 12.
• [33] Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases.Hum Pathol. 2018 Sep;79:57-65. doi: 10.1016/j.humpath.2018.05.005. Epub 2018 May 12.
• [34] Deregulation of the cyclin D1/Cdk4 retinoblastoma pathway in rat mammary gland carcinomas induced by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Cancer Res. 2003 Sep 15;63(18):5674-8.
• [35] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.