Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT70T27A)

• DOT Name: CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6)
• Synonyms: Chemokine-like factor superfamily member 6
• Gene Name: CMTM6
• Related Disease:
  Neoplasm
  Advanced cancer
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Malignant glioma
  Non-small-cell lung cancer
  Stomach cancer
  Hepatocellular carcinoma
  Clear cell renal carcinoma
• UniProt ID: CKLF6_HUMAN
• Pfam ID: PF01284
• Sequence:
  MENGAVYSPTTEEDPGPARGPRSGLAAYFFMGRLPLLRRVLKGLQLLLSLLAFICEEVVS
  QCTLCGGLYFFEFVSCSAFLLSLLILIVYCTPFYERVDTTKVKSSDFYITLGTGCVFLLA
  SIIFVSTHDRTSAEIAAIVFGFIASFMFLLDFITMLYEKRQESQLRKPENTTRAEALTEP
  LNA
• Function: Master regulator of recycling and plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Associates with both constitutive and IFNG-induced PD-L1/CD274 at recycling endosomes, where it protects PD-L1/CD274 from being targeted for lysosomal degradation, likely by preventing its STUB1-mediated ubiquitination. May stabilize PD-L1/CD274 expression on antigen presenting cells and potentiates inhibitory signaling by PDCD1/CD279, its receptor on T-cells, ultimately triggering T-cell anergy.
• Tissue Specificity: Expressed in the leukocytes, placenta and testis.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[2]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[19]

9 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 CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[15]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6).	[17]

References

• [1] Quantitative Assessment of CMTM6 in the Tumor Microenvironment and Association with Response to PD-1 Pathway Blockade in Advanced-Stage Non-Small Cell Lung Cancer.J Thorac Oncol. 2019 Dec;14(12):2084-2096. doi: 10.1016/j.jtho.2019.09.014. Epub 2019 Oct 9.
• [2] Targeting CMTM6 Suppresses Stem Cell-Like Properties and Enhances Antitumor Immunity in Head and Neck Squamous Cell Carcinoma.Cancer Immunol Res. 2020 Feb;8(2):179-191. doi: 10.1158/2326-6066.CIR-19-0394. Epub 2019 Nov 26.
• [3] Bioinformatic analysis of the prognostic value of ZNF860 in recurrence-free survival and its potential regulative network in gastric cancer.Eur Rev Med Pharmacol Sci. 2019 Jan;23(1):162-170. doi: 10.26355/eurrev_201901_16760.
• [4] CMTM6 overexpression is associated with molecular and clinical characteristics of malignancy and predicts poor prognosis in gliomas.EBioMedicine. 2018 Sep;35:233-243. doi: 10.1016/j.ebiom.2018.08.012. Epub 2018 Aug 18.
• [5] Increased CMTM6 can predict the clinical response to PD-1 inhibitors in non-small cell lung cancer patients.Oncoimmunology. 2019 Jun 14;8(10):e1629261. doi: 10.1080/2162402X.2019.1629261. eCollection 2019.
• [6] Expression and Clinical Significance of CMTM6 in Hepatocellular Carcinoma.DNA Cell Biol. 2019 Feb;38(2):193-197. doi: 10.1089/dna.2018.4513. Epub 2018 Dec 18.
• [7] An immunophenotyping of renal clear cell carcinoma with characteristics and a potential therapeutic target for patients insensitive to immune checkpoint blockade.J Cell Biochem. 2019 Aug;120(8):13330-13341. doi: 10.1002/jcb.28607. Epub 2019 Mar 27.
• [8] 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.
• [9] 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.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] 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.
• [16] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.