Details of the Drug Combination

General Information of Drug Combination (ID: DCJCMNN)

• Drug Combination Name: Vemurafenib + Bleomycin
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Vemurafenib (DM62UG5): Small molecular drug
  Bleomycin (DMNER5S): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: 786-0
  Zero Interaction Potency (ZIP) Score: 12.09
  Bliss Independence Score: 12.1
  Loewe Additivity Score: 1.58
  LHighest Single Agent (HSA) Score: 13.13

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	[7]

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	[8]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]

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	[10]

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	[5]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[6]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[6]
CD70 antigen (CD70)	OTHB2AL1	CD70_HUMAN	Decreases Expression	[13]
Melanocyte protein PMEL (PMEL)	OTCDDHHM	PMEL_HUMAN	Increases Expression	[5]
Melanoma antigen recognized by T-cells 1 (MLANA)	OT1N2S2K	MAR1_HUMAN	Increases Expression	[5]

Indication(s) of Bleomycin

Disease Entry	ICD 11	Status	REF
Cervical cancer	2C77.0	Approved	[3]
Head and neck cancer	2D42	Approved	[3]
Hodgkin lymphoma	2B30	Approved	[4]
Penile cancer	N.A.	Approved	[3]
Testicular germ cell tumor	N.A.	Approved	[3]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]
Follicular lymphoma	2A80	Investigative	[3]

Bleomycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Breaker	[18]

Bleomycin Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Bleomycin hydrolase (BLMH)	DECH1VP	BLMH_HUMAN	Metabolism	[19]

Bleomycin Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[20]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[21]
Mucin-5AC (MUC5AC)	OTJV8O04	MUC5A_HUMAN	Increases Expression	[21]
Transmembrane protein 250 (TMEM250)	OTLJ4G5G	TM250_HUMAN	Increases Expression	[14]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[22]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[23]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Decreases Expression	[14]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[15]
Unconventional myosin-Ie (MYO1E)	OTM9YSIZ	MYO1E_HUMAN	Decreases Expression	[14]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[22]
Structural maintenance of chromosomes protein 1A (SMC1A)	OT9ZMRK9	SMC1A_HUMAN	Increases Phosphorylation	[22]
7SK snRNA methylphosphate capping enzyme (MEPCE)	OTRBQEYP	MEPCE_HUMAN	Increases Expression	[14]
Transmembrane protein 87A (TMEM87A)	OT8ATDVX	TM87A_HUMAN	Increases Expression	[14]
Lipase member H (LIPH)	OTRGYLKL	LIPH_HUMAN	Decreases Expression	[14]
Abasic site processing protein HMCES (HMCES)	OTVRDL6U	HMCES_HUMAN	Decreases Expression	[14]
Small integral membrane protein 14 (SMIM14)	OT47IF19	SIM14_HUMAN	Decreases Expression	[14]
Kelch-like protein 42 (KLHL42)	OTK6WARI	KLH42_HUMAN	Increases Expression	[14]
Inactive cell surface hyaluronidase CEMIP2 (CEMIP2)	OT9I1XUO	CEIP2_HUMAN	Decreases Expression	[14]
ERBB receptor feedback inhibitor 1 (ERRFI1)	OT7VZ2IZ	ERRFI_HUMAN	Decreases Expression	[14]
Transmembrane and coiled-coil domain protein 3 (TMCC3)	OTAIQ6V6	TMCC3_HUMAN	Decreases Expression	[14]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast adenocarcinoma	DCM93CZ	MDA-MB-468	Investigative	[25]
Colon carcinoma	DCH06OI	KM12	Investigative	[25]
Invasive ductal carcinoma	DCJ4F9G	T-47D	Investigative	[25]
Adenocarcinoma	DCXJYOJ	HT29	Investigative	[1]
Astrocytoma	DCTX8I9	SNB-19	Investigative	[1]
Clear cell renal cell carcinoma	DCG9FEZ	A498	Investigative	[1]
Clear cell renal cell carcinoma	DCB9TIJ	CAKI-1	Investigative	[1]
Cutaneous melanoma	DCFXYDM	SK-MEL-5	Investigative	[1]
Glioblastoma	DCGJXCB	SNB-75	Investigative	[1]
Glioma	DCLZWWP	SF-539	Investigative	[1]
Lung adenocarcinoma	DCGVNST	MDA-MB-231	Investigative	[1]
Malignant melanoma	DCXPCF2	UACC62	Investigative	[1]
Malignant melanoma	DCA6P5H	LOX IMVI	Investigative	[1]
Melanoma	DCBKHWY	UACC-257	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] Bleomycin FDA Label
• [4] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] 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.
• [6] 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.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] 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.
• [9] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [10] Vemurafenib for the treatment of melanoma. Expert Opin Pharmacother. 2012 Dec;13(17):2533-43.
• [11] Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells. Elife. 2015 Aug 18;4:e04640. doi: 10.7554/eLife.04640.
• [12] 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.
• [13] 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.
• [14] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [15] Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells. Cell Biol Toxicol. 2022 Aug;38(4):557-575. doi: 10.1007/s10565-022-09698-1. Epub 2022 Mar 10.
• [16] An antisense oligonucleotide targeted to human Ku86 messenger RNA sensitizes M059K malignant glioma cells to ionizing radiation, bleomycin, and etoposide but not DNA cross-linking agents. Cancer Res. 2002 Oct 15;62(20):5888-96.
• [17] XRCC1 deficiency sensitizes human lung epithelial cells to genotoxicity by crocidolite asbestos and Libby amphibole. Environ Health Perspect. 2010 Dec;118(12):1707-13. doi: 10.1289/ehp.1002312. Epub 2010 Aug 11.
• [18] Bleomycin and talisomycin sequence-specific strand scission of DNA: a mechanism of double-strand cleavage. Cancer Res. 1982 Jul;42(7):2779-85.
• [19] The C-terminus of human bleomycin hydrolase is required for protection against bleomycin-induced chromosomal damage. Mutat Res. 1998 Oct 12;421(1):1-7.
• [20] Age-dependent basal level and induction capacity of copper-zinc and manganese superoxide dismutase and other scavenging enzyme activities in leukocytes from young and elderly adults. Am J Pathol. 1993 Jul;143(1):312-20.
• [21] Agents associated with lung inflammation induce similar responses in NCI-H292 lung epithelial cells. Toxicol In Vitro. 2008 Oct;22(7):1782-8.
• [22] Direct activation of ATM by resveratrol under oxidizing conditions. PLoS One. 2014 Jun 16;9(6):e97969. doi: 10.1371/journal.pone.0097969. eCollection 2014.
• [23] Distinct mechanisms of cell-kill by triapine and its terminally dimethylated derivative Dp44mT due to a loss or gain of activity of their copper(II) complexes. Biochem Pharmacol. 2014 Oct 1;91(3):312-22. doi: 10.1016/j.bcp.2014.08.006. Epub 2014 Aug 15.
• [24] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [25] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1126165