Details of the Drug Combination

General Information of Drug Combination (ID: DC7CN19)

• Drug Combination Name: MK-1775 + Erlotinib
• Indication: Amelanotic melanoma; Status: Investigative [1]
• Component Drugs:
  MK-1775 (DM3WDZ5): Small molecular drug
  Erlotinib (DMCMBHA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: A2058
  Zero Interaction Potency (ZIP) Score: 0.25
  Bliss Independence Score: 0.48
  Loewe Additivity Score: 0.02
  LHighest Single Agent (HSA) Score: 4.62

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-1775

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 2	[2]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

MK-1775 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Wee1-like protein kinase (WEE1)	TTJFOAL	WEE1_HUMAN	Inhibitor	[7]

MK-1775 Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Phosphorylation	[6]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Response To Substance	[6]

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[4]
Adult hepatocellular carcinoma	N.A.	Approved	[4]
Brain cancer	2A00	Approved	[4]
Esophageal disorder	N.A.	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Non-small-cell lung cancer	2C25.Y	Approved	[5]
Pancreatic adenocarcinoma	N.A.	Approved	[4]
Psoriasis	EA90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[4]
Pancreatic cancer	2C10	Phase 3	[5]
Colon cancer	2B90.Z	Phase 2	[5]
Ependymoma	2A00.0Y	Investigative	[4]
Neoplastic meningitis	N.A.	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]

Erlotinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[8]

Erlotinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]

Erlotinib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

Erlotinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response	[13]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DC92V49	CAOV3	Investigative	[1]
Adenocarcinoma	DCTO1SJ	NCIH1650	Investigative	[1]
Adenocarcinoma	DCEZJXP	NCIH2122	Investigative	[1]
Adenocarcinoma	DCK3IEP	NCIH520	Investigative	[1]
Adenocarcinoma	DCDA56W	COLO320DM	Investigative	[1]
Adenocarcinoma	DCMFK7Q	HCT116	Investigative	[1]
Adenocarcinoma	DCJ3FI1	HT29	Investigative	[1]
Adenocarcinoma	DCHY8DA	SW-620	Investigative	[1]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCVEAFS	ES2	Investigative	[1]
Germ cell tumour	DCKPLK7	PA1	Investigative	[1]
Large cell lung carcinoma	DC8JI6U	NCI-H460	Investigative	[1]
Malignant melanoma	DCOEWRR	A375	Investigative	[1]
Malignant melanoma	DC45ENQ	SKMEL30	Investigative	[1]
Malignant melanoma	DCMV16H	UACC62	Investigative	[1]
Mesothelioma	DC9QV02	MSTO	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DCEG4FJ	A2780	Investigative	[1]
Prostate carcinoma	DCWS8F2	VCAP	Investigative	[1]
Breast and ovarian cancer syndrome	DCVTOT1	UWB1289+BRCA1	Investigative	[14]
Breast carcinoma	DCBHNVH	KPL1	Investigative	[14]
Breast carcinoma	DCKLEMV	OCUBM	Investigative	[14]
Carcinoma	DCZLMSY	EFM192B	Investigative	[14]
Colon adenocarcinoma	DCANMCQ	LOVO	Investigative	[14]
Colon carcinoma	DCVL1HK	RKO	Investigative	[14]
Rectal adenocarcinoma	DCFIU4D	SW837	Investigative	[14]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 7702).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Erlotinib FDA Label
• [5] 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: 4920).
• [6] Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin Cancer Res. 2014 Aug 15;20(16):4274-88. doi: 10.1158/1078-0432.CCR-13-2858.
• [7] A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
• [8] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [9] Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7.
• [10] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [11] In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9.
• [12] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [13] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
• [14] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.