Details of the Drug Combination

General Information of Drug Combination (ID: DCKE86M)

• Drug Combination Name: Erlotinib + MK-4827
• Indication: Breast carcinoma; Status: Investigative [1]
• Component Drugs:
  Erlotinib (DMCMBHA): Small molecular drug
  MK-4827 (DMLYGH4): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KPL1
  Zero Interaction Potency (ZIP) Score: 8.71
  Bliss Independence Score: 10.87
  Loewe Additivity Score: 11.47
  LHighest Single Agent (HSA) Score: 13.81

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Erlotinib

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

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]

Indication(s) of MK-4827

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Phase 3	[4]
Breast cancer	2C60-2C65	Phase 2	[5]
Ewing sarcoma	2B52	Phase 1	[5]

MK-4827 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Modulator	[12]

MK-4827 Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[13]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[14]
Beta-glucuronidase (GUSB)	DEP54UE	BGLR_HUMAN	Metabolism	[14]

MK-4827 Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DC03QIJ	CAOV3	Investigative	[16]
Adenocarcinoma	DCGH1IE	OVCAR3	Investigative	[16]
Adenocarcinoma	DCJMO4P	A427	Investigative	[16]
Adenocarcinoma	DCUH9VF	NCIH2122	Investigative	[16]
Adenocarcinoma	DC19XR0	NCIH23	Investigative	[16]
Adenocarcinoma	DCG54VV	NCIH520	Investigative	[16]
Adenocarcinoma	DC5Y81L	COLO320DM	Investigative	[16]
Adenocarcinoma	DCL2ANL	DLD1	Investigative	[16]
Adenocarcinoma	DCJTYT7	HCT116	Investigative	[16]
Adenocarcinoma	DC0W83Z	HT29	Investigative	[16]
Adenocarcinoma	DC5FCN9	SW-620	Investigative	[16]
Amelanotic melanoma	DCN9VS2	A2058	Investigative	[16]
Ewing sarcoma-peripheral primitive neuroectodermal tumour	DCM6AE4	ES2	Investigative	[16]
Germ cell tumour	DCH02J5	PA1	Investigative	[16]
Large cell lung carcinoma	DC0VV6K	NCI-H460	Investigative	[16]
Malignant melanoma	DCHEDY8	A375	Investigative	[16]
Malignant melanoma	DC3POQE	HT144	Investigative	[16]
Malignant melanoma	DCG0M5A	RPMI7951	Investigative	[16]
Malignant melanoma	DCZ8NAS	SKMEL30	Investigative	[16]
Malignant melanoma	DCTFYGE	UACC62	Investigative	[16]
Non small cell carcinoma	DC4R5XF	SKMES1	Investigative	[16]
Ovarian endometrioid adenocarcinoma	DC011UA	A2780	Investigative	[16]
Ovarian serous cystadenocarcinoma	DCVUA20	SK-OV-3	Investigative	[16]
Prostate carcinoma	DC98K69	LNCAP	Investigative	[16]
Breast and ovarian cancer syndrome	DCG60RJ	UWB1289+BRCA1	Investigative	[1]
Breast carcinoma	DCWNPQ6	OCUBM	Investigative	[1]
Carcinoma	DCXXSJO	OV90	Investigative	[1]
Carcinoma	DC3VAAH	EFM192B	Investigative	[1]
Colon adenocarcinoma	DCZANBO	LOVO	Investigative	[1]
Colon carcinoma	DCGQRYB	RKO	Investigative	[1]
Invasive ductal carcinoma	DCLC4QF	T-47D	Investigative	[1]
Rectal adenocarcinoma	DCNS45Z	SW837	Investigative	[1]

References

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• [2] Erlotinib FDA Label
• [3] 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).
• [4] ClinicalTrials.gov (NCT03602859) A Phase 3 Comparison of Platinum-based Therapy With TSR-042 and Niraparib Versus Standard of Care (SOC) Platinum-based Therapy as First-line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST). U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [13] Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.
• [14] Summary of FDA-approved anticancer cytotoxic drugs at May 2019.
• [15] Autophagy up-regulated by MEK/ERK promotes the repair of DNA damage caused by aflatoxin B1. Toxicol Mech Methods. 2022 Feb;32(2):87-96. doi: 10.1080/15376516.2021.1968985. Epub 2021 Aug 26.
• [16] 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.