Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF8Y9XY)

• DOT Name: Growth factor receptor-bound protein 7 (GRB7)
• Synonyms: B47; Epidermal growth factor receptor GRB-7; GRB7 adapter protein
• Gene Name: GRB7
• Related Disease:
  HER2/NEU overexpressing breast cancer
  Invasive breast carcinoma
  Adenocarcinoma
  Advanced cancer
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
  Clear cell renal carcinoma
  Congenital adrenal hyperplasia
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Papillary renal cell carcinoma
  Prostate cancer
  Prostate neoplasm
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Stomach cancer
  Testicular germ cell tumor
  Carcinoma of esophagus
  Hereditary hemochromatosis
  Triple negative breast cancer
• UniProt ID: GRB7_HUMAN
• PDB ID: 1MW4; 1WGR; 2L4K; 2QMS; 3PQZ; 4WWQ; 4X6S; 5D0J; 5EEL; 5EEQ; 5TYI; 5U06; 5U1Q; 7MP3
• Pfam ID: PF08947 ; PF00169 ; PF00788 ; PF00017
• Sequence:
  MELDLSPPHLSSSPEDLCPAPGTPPGTPRPPDTPLPEEVKRSQPLLIPTTGRKLREEERR
  ATSLPSIPNPFPELCSPPSQSPILGGPSSARGLLPRDASRPHVVKVYSEDGACRSVEVAA
  GATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAWPVGGDSRFV
  FRKNFAKYELFKSSPHSLFPEKMVSSCLDAHTGISHEDLIQNFLNAGSFPEIQGFLQLRG
  SGRKLWKRFFCFLRRSGLYYSTKGTSKDPRHLQYVADVNESNVYVVTQGRKLYGMPTDFG
  FCVKPNKLRNGHKGLRIFCSEDEQSRTCWLAAFRLFKYGVQLYKNYQQAQSRHLHPSCLG
  SPPLRSASDNTLVAMDFSGHAGRVIENPREALSVALEEAQAWRKKTNHRLSLPMPASGTS
  LSAAIHRTQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHY
  LILPSEEEGRLYFSMDDGQTRFTDLLQLVEFHQLNRGILPCLLRHCCTRVAL
• Function: Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress.
• Reactome Pathway:
  Signaling by SCF-KIT (R-HSA-1433557)
  Downstream signal transduction (R-HSA-186763)
  Tie2 Signaling (R-HSA-210993)
  RET signaling (R-HSA-8853659)
  RND1 GTPase cycle (R-HSA-9696273)
  GRB7 events in ERBB2 signaling (R-HSA-1306955)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
HER2/NEU overexpressing breast cancer	DISYKID5	Definitive	Biomarker	[1]
Invasive breast carcinoma	DISANYTW	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[8]
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	DISMTRY0	Strong	Genetic Variation	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[10]
Congenital adrenal hyperplasia	DISG873W	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[18]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[19]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[11]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[20]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[10]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[22]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[14]
Testicular germ cell tumor	DIS5RN24	Strong	Altered Expression	[23]
Carcinoma of esophagus	DISS6G4D	moderate	Biomarker	[18]
Hereditary hemochromatosis	DISVG5MT	Limited	Biomarker	[24]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Growth factor receptor-bound protein 7 (GRB7) decreases the response to substance of Arsenic trioxide.	[39]
Afimoxifene	DMFORDT	Phase 2	Growth factor receptor-bound protein 7 (GRB7) decreases the response to substance of Afimoxifene.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[26]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Growth factor receptor-bound protein 7 (GRB7).	[29]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Growth factor receptor-bound protein 7 (GRB7).	[30]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[27]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Growth factor receptor-bound protein 7 (GRB7).	[31]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[32]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Growth factor receptor-bound protein 7 (GRB7).	[37]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Growth factor receptor-bound protein 7 (GRB7).	[38]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Growth factor receptor-bound protein 7 (GRB7).	[27]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Growth factor receptor-bound protein 7 (GRB7).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Growth factor receptor-bound protein 7 (GRB7).	[36]

References

• [1] Epigenetically altered miR?93a?p promotes HER2 positive breast cancer aggressiveness by targeting GRB7.Int J Mol Med. 2019 Jun;43(6):2352-2360. doi: 10.3892/ijmm.2019.4167. Epub 2019 Apr 15.
• [2] GRB7 Expression and Correlation With HER2 Amplification in Invasive Breast Carcinoma.Appl Immunohistochem Mol Morphol. 2017 Sep;25(8):553-558. doi: 10.1097/PAI.0000000000000349.
• [3] Varied pathways of stage IA lung adenocarcinomas discovered by integrated gene expression analysis.Int J Biol Sci. 2011 Apr 28;7(5):551-66. doi: 10.7150/ijbs.7.551.
• [4] Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target.Cells. 2019 May 10;8(5):435. doi: 10.3390/cells8050435.
• [5] Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma.Int J Cancer. 2004 Dec 10;112(5):747-53. doi: 10.1002/ijc.20411.
• [6] GRB7 dependent proliferation of basal-like, HER-2 positive human breast cancer cell lines is mediated in part by HER-1 signaling.Mol Carcinog. 2019 May;58(5):699-707. doi: 10.1002/mc.22963. Epub 2019 Jan 28.
• [7] Relevance of breast cancer antiestrogen resistance genes in human breast cancer progression and tamoxifen resistance.J Clin Oncol. 2009 Feb 1;27(4):542-9. doi: 10.1200/JCO.2008.17.1462. Epub 2008 Dec 15.
• [8] Grb7 is over-expressed in cervical cancer and facilitate invasion and inhibit apoptosis in cervical cancer cells.Pathol Res Pract. 2017 Sep;213(9):1180-1184. doi: 10.1016/j.prp.2017.05.013. Epub 2017 Jul 26.
• [9] The HLA-A3, Cw6,B47,DR7 extended haplotypes in salt losing 21-hydroxylase deficiency and in the Old Order Amish: identical class I antigens and class II alleles with at least two crossover sites in the class III region.Tissue Antigens. 1995 Sep;46(3 ( Pt 1)):163-72. doi: 10.1111/j.1399-0039.1995.tb03115.x.
• [10] Integrated molecular analysis of clear-cell renal cell carcinoma.Nat Genet. 2013 Aug;45(8):860-7. doi: 10.1038/ng.2699. Epub 2013 Jun 24.
• [11] Grb7 gene amplification and protein expression by FISH and IHC in ovarian cancer.Int J Clin Exp Pathol. 2015 Sep 1;8(9):11296-304. eCollection 2015.
• [12] 17q12-21 - the pursuit of targeted therapy in breast cancer.Cancer Treat Rev. 2010 May;36(3):224-9. doi: 10.1016/j.ctrv.2009.12.007. Epub 2010 Jan 25.
• [13] An Integrative Analysis to Identify Driver Genes in Esophageal Squamous Cell Carcinoma.PLoS One. 2015 Oct 14;10(10):e0139808. doi: 10.1371/journal.pone.0139808. eCollection 2015.
• [14] Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon.Int J Oncol. 2004 Apr;24(4):757-63.
• [15] Role of growth factor receptor bound protein 7 in hepatocellular carcinoma.Mol Cancer Res. 2007 Jul;5(7):667-73. doi: 10.1158/1541-7786.MCR-06-0282.
• [16] A novel variant of human Grb7 is associated with invasive esophageal carcinoma.J Clin Invest. 1998 Aug 15;102(4):821-7. doi: 10.1172/JCI2921.
• [17] Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target.J Med Chem. 2017 Nov 22;60(22):9349-9359. doi: 10.1021/acs.jmedchem.7b01320. Epub 2017 Nov 10.
• [18] ERBB2 amplifications in esophageal adenocarcinoma.Ann Thorac Surg. 2004 Nov;78(5):1790-800. doi: 10.1016/j.athoracsur.2004.05.037.
• [19] Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways.Theranostics. 2018 Jan 1;8(2):423-436. doi: 10.7150/thno.22377. eCollection 2018.
• [20] Specific peptide ligand for Grb7 signal transduction protein and pancreatic cancer metastasis.J Natl Cancer Inst. 2006 Apr 5;98(7):491-8. doi: 10.1093/jnci/djj105.
• [21] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [22] Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease.Leukemia. 2004 Dec;18(12):1948-50. doi: 10.1038/sj.leu.2403512.
• [23] Candidate genes for testicular cancer evaluated by in situ protein expression analyses on tissue microarrays.Neoplasia. 2003 Sep-Oct;5(5):397-404. doi: 10.1016/s1476-5586(03)80042-8.
• [24] An HLA study in 74 Danish haemochromatosis patients and in 21 of their families.Clin Genet. 1992 Jan;41(1):6-11. doi: 10.1111/j.1399-0004.1992.tb03619.x.
• [25] Context-dependent role of Grb7 in HER2+ve and triple-negative breast cancer cell lines.Breast Cancer Res Treat. 2014 Feb;143(3):593-603. doi: 10.1007/s10549-014-2838-5. Epub 2014 Jan 25.
• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [30] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [31] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [32] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [33] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [34] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [35] 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.
• [36] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [37] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [38] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [39] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [40] Functional identification of genes causing estrogen independence of human breast cancer cells. Breast Cancer Res Treat. 2009 Mar;114(1):23-30. doi: 10.1007/s10549-008-9969-5. Epub 2008 Mar 21.