Details of the Drug Combination

General Information of Drug Combination (ID: DC1XTHT)

• Drug Combination Name: Everolimus + Letrozole
• Indication: Postmenopausal Women; Status: Phase 1 [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  Letrozole (DMH07Y3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Everolimus

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Advanced/metastatic breast cancer	2C60	Approved	[3]
Brainstem neoplasm	N.A.	Approved	[2]
Breast carcinoma	N.A.	Approved	[2]
Graft-versus-host disease	4B24	Approved	[2]
Intracranial meningioma	N.A.	Approved	[2]
Leukemia	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Mucosal melanoma	N.A.	Approved	[2]
Multiple sclerosis	8A40	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[2]
Renal cell carcinoma	2C90	Approved	[4]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Tuberous sclerosis	LD2D.2	Approved	[2]
Kidney cancer	2C90.0	Phase 3	[4]
Castration-resistant prostate carcinoma	N.A.	Investigative	[2]
Colon cancer	2B90.Z	Investigative	[2]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[5]
Neuroblastoma	2D11.2	Investigative	[2]
Pancreatic acinar cell carcinoma	N.A.	Investigative	[2]
Polycystic kidney disease	GB8Y	Investigative	[2]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[5]

Everolimus Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase mTOR (mTOR)	TTCJG29	MTOR_HUMAN	Inhibitor	[8]
HUMAN mammalian target of rapamycin (mTOR)	TT7HQAF	MTOR_HUMAN	Inhibitor	[5]

Everolimus Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Everolimus 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]

Indication(s) of Letrozole

Disease Entry	ICD 11	Status	REF
Estrogen-receptor positive breast cancer	N.A.	Approved	[6]
Hormonally-responsive breast cancer	2C60-2C65	Approved	[7]

Letrozole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[11]

Letrozole Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Aromatase (CYP19A1)	DEQX145	CP19A_HUMAN	Metabolism	[13]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[14]

Letrozole Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[15]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[16]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Oxidation	[16]
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[17]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[18]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[19]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[19]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[20]
Leukemia inhibitory factor (LIF)	OTO46S5S	LIF_HUMAN	Increases Expression	[18]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[21]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[22]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[22]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[23]
Leukemia inhibitory factor receptor (LIFR)	OT36W9O5	LIFR_HUMAN	Increases Expression	[18]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[20]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[22]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Activity	[24]
Fibroblast growth factor 22 (FGF22)	OTVIX6J0	FGF22_HUMAN	Increases Expression	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Recurrent Endometrial Carcinoma	DC8R6NG	N. A.	Phase 2	[25]
Advanced Malignant Solid Neoplasm	DCBYD0M	N. A.	Phase 1	[26]

References

• [1] ClinicalTrials.gov (NCT01231659) Safety and Efficacy of RAD001 (Everolimus) in Combination With Letrozole in the Treatment of Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer
• [2] Everolimus FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 5889).
• [5] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [6] Letrozole FDA Label
• [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. (Ligand id: 5209).
• [8] Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9.
• [9] Closer to the Site of Action: Everolimus Concentrations in Peripheral Blood Mononuclear Cells Correlate Well With Whole Blood Concentrations. Ther Drug Monit. 2015 Oct;37(5):675-80.
• [10] The evolving experience using everolimus in clinical transplantation. Transplant Proc. 2004 Mar;36(2 Suppl):495S-499S.
• [11] Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
• [12] Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer Chemother Pharmacol. 2009 Oct;64(5):867-75.
• [13] Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
• [14] Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379.
• [15] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [16] Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2009 Nov;39(11):795-802. doi: 10.3109/00498250903171395.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [18] Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome. Fertil Steril. 2011 Oct;96(4):1051-6. doi: 10.1016/j.fertnstert.2011.07.1092.
• [19] Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
• [20] Aromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol. 2005 May;95(1-5):83-9. doi: 10.1016/j.jsbmb.2005.04.010.
• [21] Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018 Jan 1;338:182-190. doi: 10.1016/j.taap.2017.11.020. Epub 2017 Nov 24.
• [22] Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005 Jul 15;11(14):5319-28. doi: 10.1158/1078-0432.CCR-04-2402.
• [23] Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010 Nov;124(1):79-88. doi: 10.1007/s10549-009-0714-5. Epub 2010 Jan 7.
• [24] Comparison of lanosterol-14 alpha-demethylase (CYP51) of human and Candida albicans for inhibition by different antifungal azoles. Toxicology. 2006 Nov 10;228(1):24-32. doi: 10.1016/j.tox.2006.08.007. Epub 2006 Aug 12.
• [25] ClinicalTrials.gov (NCT03008408) A Phase II, Two-Arm Study of Everolimus and Letrozole, +/- Ribociclib (Lee011) in Patients With Advanced or Recurrent Endometrial Carcinoma
• [26] ClinicalTrials.gov (NCT02152943) Everolimus, Letrozole and Trastuzumab in HR- and HER2/Neu-positive Patients