Details of the Drug Combination

General Information of Drug Combination (ID: DC1ZH7A)

• Drug Combination Name: MK-5108 + Erlotinib
• Indication: Adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  MK-5108 (DMFGYKS): Small molecular drug
  Erlotinib (DMCMBHA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: CAOV3
  Zero Interaction Potency (ZIP) Score: 0.36
  Bliss Independence Score: 0.38
  Loewe Additivity Score: 3.35
  LHighest Single Agent (HSA) Score: 6.39

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MK-5108

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

MK-5108 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aurora kinase B (AURKB)	TT5LS6T	AURKB_HUMAN	Inhibitor	[5]
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[5]

Indication(s) of Erlotinib

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

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	[6]

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	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]

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	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]

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	[11]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast and ovarian cancer syndrome	DCOBHS3	UWB1289	Investigative	[12]
Breast and ovarian cancer syndrome	DCS8BJ2	UWB1289+BRCA1	Investigative	[12]
Breast carcinoma	DCFUGT7	KPL1	Investigative	[12]
Breast carcinoma	DCIC8RS	OCUBM	Investigative	[12]
Carcinoma	DCDD06T	EFM192B	Investigative	[12]
Colon adenocarcinoma	DCN4N4F	LOVO	Investigative	[12]
Colon carcinoma	DC3MKVG	RKO	Investigative	[12]
Invasive ductal carcinoma	DCTE8LK	T-47D	Investigative	[12]
Rectal adenocarcinoma	DCI88SZ	SW837	Investigative	[12]
Adenocarcinoma	DCM4Q20	OVCAR3	Investigative	[1]
Adenocarcinoma	DCLHP24	A427	Investigative	[1]
Adenocarcinoma	DCG37J1	NCIH1650	Investigative	[1]
Adenocarcinoma	DCPXROO	NCIH2122	Investigative	[1]
Adenocarcinoma	DC76B4I	NCIH23	Investigative	[1]
Adenocarcinoma	DC5TJ1Q	NCIH520	Investigative	[1]
Adenocarcinoma	DCYSN5X	COLO320DM	Investigative	[1]
Adenocarcinoma	DCK4QKP	DLD1	Investigative	[1]
Adenocarcinoma	DCS3U2A	HT29	Investigative	[1]
Adenocarcinoma	DCKVT7V	SW-620	Investigative	[1]
Adenocarcinoma	DCXAF9D	HCT116	Investigative	[1]
Amelanotic melanoma	DCIO91C	A2058	Investigative	[1]
Germ cell tumour	DCBZQZR	PA1	Investigative	[1]
Large cell lung carcinoma	DC1OL2T	NCI-H460	Investigative	[1]
Malignant melanoma	DCX2EF7	HT144	Investigative	[1]
Malignant melanoma	DCKGI43	RPMI7951	Investigative	[1]
Malignant melanoma	DCQV03K	SKMEL30	Investigative	[1]
Malignant melanoma	DCVANOK	UACC62	Investigative	[1]
Malignant melanoma	DC4KM6B	A375	Investigative	[1]
Mesothelioma	DCR914L	MSTO	Investigative	[1]
Ovarian endometrioid adenocarcinoma	DC51XGC	A2780	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCA4D1Y	SK-OV-3	Investigative	[1]
Prostate carcinoma	DC0PT5I	LNCAP	Investigative	[1]
Prostate carcinoma	DCEATRI	VCAP	Investigative	[1]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] ClinicalTrials.gov (NCT00543387) Treatment of Participants With Advanced and/or Refractory Solid Tumors (MK-5108-001 AM4). U.S. National Institutes of Health.
• [3] Erlotinib FDA Label
• [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: 4920).
• [5] 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.
• [6] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [7] 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.
• [8] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [9] 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.
• [10] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [11] 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.
• [12] 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.