Details of the Drug Combination

General Information of Drug Combination (ID: DCGZUC6)

• Drug Combination Name: Selumetinib + Erlotinib
• Indication: Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Selumetinib (DMC7W6R): Small molecular drug
  Erlotinib (DMCMBHA): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Selumetinib

Disease Entry	ICD 11	Status	REF
Neurofibromatosis type 1	LD2D.10	Approved	[2]
Melanoma	2C30	Phase 3	[3]
Thyroid cancer	2D10	Phase 3	[4]
Non-small-cell lung cancer	2C25.Y	Phase 2	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[6]
Solid tumour/cancer	2A00-2F9Z	Investigative	[7]

Selumetinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[10]
ERK activator kinase 1 (MEK1)	TTIDAPM	MP2K1_HUMAN	Inhibitor	[4]
ERK activator kinase 2 (MEK2)	TTTW2NY	MP2K2_HUMAN	Inhibitor	[4]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[6]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[6]

Selumetinib Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[11]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Decreases Phosphorylation	[12]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Activity	[12]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Activity	[12]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Activity	[12]
Cyclic AMP-responsive element-binding protein 1 (CREB1)	OT1MDLA1	CREB1_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[13]

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[8]
Adult hepatocellular carcinoma	N.A.	Approved	[8]
Brain cancer	2A00	Approved	[8]
Esophageal disorder	N.A.	Approved	[8]
Lung cancer	2C25.0	Approved	[8]
Non-small-cell lung cancer	2C25.Y	Approved	[9]
Pancreatic adenocarcinoma	N.A.	Approved	[8]
Psoriasis	EA90	Approved	[8]
Salivary gland squamous cell carcinoma	N.A.	Approved	[8]
Pancreatic cancer	2C10	Phase 3	[9]
Colon cancer	2B90.Z	Phase 2	[9]
Ependymoma	2A00.0Y	Investigative	[8]
Neoplastic meningitis	N.A.	Investigative	[8]
Neuroblastoma	2D11.2	Investigative	[8]

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	[14]

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	[15]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[16]

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	[17]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]

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	[19]

References

• [1] ClinicalTrials.gov (NCT00600496) A Phase I, Open-Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD6244 (ARRY-142886)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] ClinicalTrials.gov (NCT01933932) Assess Efficacy & Safety of Selumetinib in Combination With Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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: 5665).
• [6] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [7] 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: 1479).
• [8] Erlotinib FDA Label
• [9] 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).
• [10] Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.Br J Cancer.2012 May 8;106(10):1648-59.
• [11] Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
• [12] Ursonic acid exerts inhibitory effects on matrix metalloproteinases via ERK signaling pathway. Chem Biol Interact. 2020 Jan 5;315:108910. doi: 10.1016/j.cbi.2019.108910. Epub 2019 Nov 29.
• [13] The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition. Br J Cancer. 2012 Apr 10;106(8):1386-94. doi: 10.1038/bjc.2012.70. Epub 2012 Mar 13.
• [14] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [15] 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.
• [16] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [17] 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.
• [18] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [19] 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.