Details of the Drug Combination

General Information of Drug Combination (ID: DCBJ5J9)

• Drug Combination Name: Vemurafenib + Raloxifene
• Indication: Lung adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Vemurafenib (DM62UG5): Small molecular drug
  Raloxifene (DMDKF3M): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: EKVX
  Zero Interaction Potency (ZIP) Score: 3.42
  Bliss Independence Score: 5.66
  Loewe Additivity Score: 3.56
  LHighest Single Agent (HSA) Score: 3.26

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vemurafenib

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

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	[3]

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	[6]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[7]

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	[8]

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	[4]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[9]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[10]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[5]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[5]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[11]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[4]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[4]

Indication(s) of Raloxifene

Disease Entry	ICD 11	Status	REF
Osteoporosis	FB83.0	Approved	[3]

Raloxifene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR)	TTZAYWL	ESR1_HUMAN	Modulator	[12]

Raloxifene Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Raloxifene Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCNY104	MDA-MB-468	Investigative	[17]
Carcinoma	DCOMO3U	MCF7	Investigative	[17]
Invasive ductal carcinoma	DC8II47	HS 578T	Investigative	[17]
Invasive ductal carcinoma	DCIZAED	BT-549	Investigative	[17]
Invasive ductal carcinoma	DCVO64L	T-47D	Investigative	[17]
Adenocarcinoma	DCT21A4	DU-145	Investigative	[1]
Adenocarcinoma	DCMEGOI	OVCAR3	Investigative	[1]
Adenocarcinoma	DCSM29I	A549	Investigative	[1]
Adenocarcinoma	DCU59AE	HCT116	Investigative	[1]
Astrocytoma	DC37E6D	SNB-19	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCP38FI	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCS3DOS	K-562	Investigative	[1]
Glioblastoma	DCRR70K	SNB-75	Investigative	[1]
Glioma	DCO73N6	SF-539	Investigative	[1]
Glioma	DCSVOSO	SF-268	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCOKXJM	OVCAR-8	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCAPZ67	OVCAR-4	Investigative	[1]
High grade ovarian serous adenocarcinoma	DC9RZS7	NCI\\/ADR-RES	Investigative	[1]
Large cell lung carcinoma	DC8FJB0	NCI-H460	Investigative	[1]
Lung adenocarcinoma	DC5ERI8	MDA-MB-231	Investigative	[1]
Lung adenocarcinoma	DC683PV	NCI-H522	Investigative	[1]
Malignant melanoma	DCI6IDY	LOX IMVI	Investigative	[1]
Melanoma	DCUSHKP	SK-MEL-2	Investigative	[1]
Melanoma	DC9RYK0	UACC-257	Investigative	[1]
Melanoma	DC6GNXZ	MALME-3M	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCGAX2H	NCI-H322M	Investigative	[1]
Non-small cell lung carcinoma	DC6JHES	HOP-92	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCY95VW	SK-OV-3	Investigative	[1]
Papillary renal cell carcinoma	DC9QB02	ACHN	Investigative	[1]
Plasma cell myeloma	DCEAIH5	RPMI-8226	Investigative	[1]
Pleural epithelioid mesothelioma	DCA7WKK	NCI-H226	Investigative	[1]
Prostate carcinoma	DC9SLJS	PC-3	Investigative	[1]
Renal cell carcinoma	DC1Z0UZ	SN12C	Investigative	[1]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125976
• [2] 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).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [8] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [9] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [10] 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.
• [11] 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.
• [12] 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. (Target id: 620).
• [13] Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment. Transl Res. 2012 Oct;160(4):298-308.
• [14] The role of P-glycoprotein in the bioactivation of raloxifene. Drug Metab Dispos. 2006 Dec;34(12):2073-8.
• [15] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [16] Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. Cancer Prev Res (Phila). 2013 Jul;6(7):719-30.
• [17] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165