Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRJ679P)

• DOT Name: Fibroblast growth factor 6 (FGF6)
• Synonyms: FGF-6; Heparin secretory-transforming protein 2; HST-2; HSTF-2; Heparin-binding growth factor 6; HBGF-6
• Gene Name: FGF6
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Amyotrophic lateral sclerosis type 1
  Carcinoma
  Familial amyotrophic lateral sclerosis
  Lymphoma
  Medulloblastoma
  Pediatric lymphoma
  Prostate cancer
  Prostate carcinoma
  Systemic sclerosis
  Osteoarthritis
  Neoplasm
  Neuroblastoma
• UniProt ID: FGF6_HUMAN
• Pfam ID: PF00167
• Sequence:
  MALGQKLFITMSRGAGRLQGTLWALVFLGILVGMVVPSPAGTRANNTLLDSRGWGTLLSR
  SRAGLAGEIAGVNWESGYLVGIKRQRRLYCNVGIGFHLQVLPDGRISGTHEENPYSLLEI
  STVERGVVSLFGVRSALFVAMNSKGRLYATPSFQEECKFRETLLPNNYNAYESDLYQGTY
  IALSKYGRVKRGSKVSPIMTVTHFLPRI
• Function: Plays an important role in the regulation of cell proliferation, cell differentiation, angiogenesis and myogenesis, and is required for normal muscle regeneration.
• Tissue Specificity: Leukemia cell lines with platelet/ megakaryocytic differentiation potential.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Regulation of actin cytoskeleton (hsa04810)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Melanoma (hsa05218)
  Breast cancer (hsa05224)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  (FGFR2)
  (FGFR4)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by activated point mutants of FGFR1 (R-HSA-1839122)
  FGFR4 ligand binding and activation (R-HSA-190322)
  FGFR1c ligand binding and activation (R-HSA-190373)
  FGFR2c ligand binding and activation (R-HSA-190375)
  Activated point mutants of FGFR2 (R-HSA-2033519)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Phospholipase C-mediated cascade (R-HSA-5654219)
  Phospholipase C-mediated cascade (R-HSA-5654221)
  Phospholipase C-mediated cascade (R-HSA-5654228)
  Downstream signaling of activated FGFR1 (R-HSA-5654687)
  SHC-mediated cascade (R-HSA-5654688)
  PI-3K cascade (R-HSA-5654689)
  FRS-mediated FGFR1 signaling (R-HSA-5654693)
  PI-3K cascade (R-HSA-5654695)
  SHC-mediated cascade (R-HSA-5654699)
  FRS-mediated FGFR2 signaling (R-HSA-5654700)
  FRS-mediated FGFR4 signaling (R-HSA-5654712)
  SHC-mediated cascade (R-HSA-5654719)
  PI-3K cascade (R-HSA-5654720)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  Signaling by FGFR2 in disease (R-HSA-5655253)
  Signaling by FGFR1 in disease (R-HSA-5655302)
  RAF/MAP kinase cascade (R-HSA-5673001)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[2]
Lymphoma	DISN6V4S	Strong	Biomarker	[1]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[4]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[6]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[7]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Fibroblast growth factor 6 (FGF6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibroblast growth factor 6 (FGF6).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fibroblast growth factor 6 (FGF6).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Fibroblast growth factor 6 (FGF6).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Fibroblast growth factor 6 (FGF6).	[13]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Fibroblast growth factor 6 (FGF6).	[14]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the expression of Fibroblast growth factor 6 (FGF6).	[16]

References

• [1] Pipeline for large-scale microdroplet bisulfite PCR-based sequencing allows the tracking of hepitype evolution in tumors.PLoS One. 2011;6(7):e21332. doi: 10.1371/journal.pone.0021332. Epub 2011 Jul 5.
• [2] Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
• [3] Analysis of T-cell receptor V region gene usage of cytotoxic T-lymphocytes and tumor-infiltrating lymphocytes derived from human autologous gastric signet ring cell carcinomas.Cancer Res. 1993 Jul 1;53(13):3078-84.
• [4] Antitumor activity of fibroblast growth factors (FGFs) for medulloblastoma may correlate with FGF receptor expression and tumor variant.Clin Cancer Res. 2002 Jan;8(1):246-57.
• [5] Aberrant fibroblast growth factor receptor signaling in bladder and other cancers.Differentiation. 2007 Nov;75(9):831-42. doi: 10.1111/j.1432-0436.2007.00210.x. Epub 2007 Aug 14.
• [6] A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene.Blood. 2019 Apr 25;133(17):1888-1898. doi: 10.1182/blood-2018-10-879585. Epub 2019 Feb 27.
• [7] The role of the fibroblast growth factor family in bone-related diseases.Chem Biol Drug Des. 2019 Oct;94(4):1740-1749. doi: 10.1111/cbdd.13588. Epub 2019 Aug 4.
• [8] Human hst-2 (FGF-6) oncogene: cDNA cloning and characterization.Oncogene. 1992 Feb;7(2):303-9.
• [9] DNA hypomethylation affects cancer-related biological functions and genes relevant in neuroblastoma pathogenesis.PLoS One. 2012;7(11):e48401. doi: 10.1371/journal.pone.0048401. Epub 2012 Nov 7.
• [10] 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.
• [11] Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21737-42. doi: 10.1073/pnas.1007863107. Epub 2010 Nov 22.
• [12] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [13] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [14] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [15] 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.
• [16] Induction of fibroblast growth factor-9 and interleukin-1alpha gene expression by motorcycle exhaust particulate extracts and benzo(a)pyrene in human lung adenocarcinoma cells. Toxicol Sci. 2005 Oct;87(2):483-96. doi: 10.1093/toxsci/kfi251. Epub 2005 Jul 7.