Details of the Drug Combination

General Information of Drug Combination (ID: DC2LEYC)

• Drug Combination Name: Dacarbazine + Vemurafenib
• Indication: Astrocytoma; Status: Investigative [1]
• Component Drugs:
  Dacarbazine (DMNPZL4): Small molecular drug
  Vemurafenib (DM62UG5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: SNB-19
  Zero Interaction Potency (ZIP) Score: 2.71
  Bliss Independence Score: 4.17
  Loewe Additivity Score: 0.6
  LHighest Single Agent (HSA) Score: 1.82

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dacarbazine

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[2]
Astrocytoma	2A00.0Y	Approved	[2]
Brain disease	8C70-8E61	Approved	[2]
Central nervous system disease	8A04-8D87	Approved	[2]
Glioblastoma	2A00	Approved	[2]
Gliosarcoma	N.A.	Approved	[2]
Melanoma	2C30	Approved	[3]
Classic Hodgkin lymphoma	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]

Dacarbazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[6]

Dacarbazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[8]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[9]

Dacarbazine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Increases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[5]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Decreases Activity	[11]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[12]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Response To Substance	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Response To Substance	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Response To Substance	[14]
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)	OTS3FVTY	M3K1_HUMAN	Decreases Response To Substance	[14]

Indication(s) of Vemurafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[4]

Vemurafenib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase B-raf (BRAF)	TTWCGQT	BRAF_HUMAN	Modulator	[17]

Vemurafenib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[19]

Vemurafenib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]

Vemurafenib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Affects Expression	[15]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[21]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[22]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[16]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[23]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[15]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCMBBNW	HCT-15	Investigative	[1]
Adult acute myeloid leukemia	DCYGKN6	HL-60(TB)	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCOSCZA	CCRF-CEM	Investigative	[1]
Glioma	DCW0J9I	SF-295	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCN2DJ3	OVCAR-8	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCGKNBB	NCI-H322M	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Dacarbazine FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075259.
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5893).
• [5] Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther. 2003 Aug;2(8):753-63.
• [6] Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mono... Melanoma Res. 2011 Dec;21(6):502-8.
• [7] Study on mesenchymal stem cells mediated enzyme-prodrug gene CYP1A2 targeting anti-tumor effect. Zhonghua Xue Ye Xue Za Zhi. 2009 Oct;30(10):667-71.
• [8] Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7.
• [9] Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation. Clin Cancer Res. 2001 Dec;7(12):4239-44.
• [10] Serum bcl-2 and survivin levels in melanoma. Melanoma Res. 2004 Dec;14(6):543-6. doi: 10.1097/00008390-200412000-00017.
• [11] Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer. Int J Cancer. 2003 Feb 20;103(5):686-92. doi: 10.1002/ijc.10849.
• [12] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [13] Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies. Cancer Chemother Pharmacol. 2008 Mar;61(3):377-93. doi: 10.1007/s00280-007-0480-1. Epub 2007 May 23.
• [14] Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo. J Clin Oncol. 2004 Jun 1;22(11):2092-100. doi: 10.1200/JCO.2004.11.070. Epub 2004 May 3.
• [15] PLX4032 Mediated Melanoma Associated Antigen Potentiation in Patient Derived Primary Melanoma Cells. J Cancer. 2015 Oct 29;6(12):1320-30. doi: 10.7150/jca.11126. eCollection 2015.
• [16] Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016 Mar 1;35(5):462-78. doi: 10.15252/embj.201592081. Epub 2015 Dec 14.
• [17] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [18] Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci. 2014;17(1):154-68.
• [19] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [20] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [21] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [22] Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget. 2016 Jan 26;7(4):4428-41. doi: 10.18632/oncotarget.6599.
• [23] Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.