Details of the Drug Combination

General Information of Drug Combination (ID: DCL5AZI)

• Drug Combination Name: Everolimus + Exemestane
• Indication: Metastatic Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Everolimus (DM8X2EH): Small molecular drug
  Exemestane (DM9HPW3): 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 Exemestane

Disease Entry	ICD 11	Status	REF
Hormonally-responsive breast cancer	2C60-2C65	Approved	[6]
Male breast carcinoma	N.A.	Investigative	[7]

Exemestane Interacts with 1 DTT Molecule(s)

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

Exemestane Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]

Exemestane Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[13]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Expression	[14]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Increases Expression	[14]
Myb-related protein B (MYBL2)	OTZ3JX8Q	MYBB_HUMAN	Increases Expression	[15]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Affects Localization	[16]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[17]
Amphiregulin (AREG)	OTJFOR67	AREG_HUMAN	Increases Expression	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCG2)	OTGVC9MY	PLCG2_HUMAN	Increases Expression	[15]
Homeobox protein Hox-D11 (HOXD11)	OT9XGA4G	HXD11_HUMAN	Increases Expression	[15]
Pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1)	OTNBHULA	PACR_HUMAN	Increases Expression	[15]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[18]
Kallikrein-7 (KLK7)	OTIWGMO2	KLK7_HUMAN	Increases Expression	[15]
Disabled homolog 2 (DAB2)	OTRMQTMZ	DAB2_HUMAN	Increases Expression	[15]
CD83 antigen (CD83)	OT1V4WQF	CD83_HUMAN	Increases Expression	[15]
Unconventional myosin-IXb (MYO9B)	OTQ94R5K	MYO9B_HUMAN	Increases Expression	[15]
RRP12-like protein (RRP12)	OTQQAEH4	RRP12_HUMAN	Increases Expression	[15]
Dynein axonemal assembly factor 9 (DNAAF9)	OTTKWWQU	DAAF9_HUMAN	Increases Expression	[15]
E3 ubiquitin-protein ligase RNF123 (RNF123)	OTL59S8J	RN123_HUMAN	Increases Expression	[15]
Osteopetrosis-associated transmembrane protein 1 (OSTM1)	OTKNJDH7	OSTM1_HUMAN	Increases Expression	[15]
Glypican-2 (GPC2)	OT3WSQE1	GPC2_HUMAN	Increases Expression	[15]
Tumor necrosis factor receptor superfamily member 14 (TNFRSF14)	OTB82PFO	TNR14_HUMAN	Increases Expression	[15]
Integrator complex subunit 4 (INTS4)	OT5JQ913	INT4_HUMAN	Increases Expression	[15]
Inositol polyphosphate 5-phosphatase K (INPP5K)	OTQFLQKA	INP5K_HUMAN	Increases Expression	[15]
ATP-binding cassette sub-family G member 4 (ABCG4)	OT2XJIOG	ABCG4_HUMAN	Increases Expression	[15]
TRIO and F-actin-binding protein (TRIOBP)	OTGB5WHC	TARA_HUMAN	Increases Expression	[15]
TBC1 domain family member 17 (TBC1D17)	OT75ZWLB	TBC17_HUMAN	Increases Expression	[15]
Kinesin-like protein KIF13B (KIF13B)	OTAFS1YV	KI13B_HUMAN	Increases Expression	[15]
Transcription factor COE1 (EBF1)	OTZ61YYH	COE1_HUMAN	Increases Expression	[15]
Meteorin (METRN)	OTI2645G	METRN_HUMAN	Increases Expression	[15]
Solute carrier family 13 member 4 (SLC13A4)	OTP3N8N3	S13A4_HUMAN	Increases Expression	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast Cancer	DC4MTXP	N. A.	Phase 1	[19]
Neoplasms	DCHZ936	N. A.	Phase 1	[20]
Breast Cancer	DCKTQTO	N. A.	Phase 1	[21]

References

• [1] ClinicalTrials.gov (NCT01626222) 4EVER - Efficacy, Safety, Health Economics, Translational Research of Postmenopausal Women With Estrogen Receptor Positive 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] 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: 7073).
• [7] Exemestane FDA Label
• [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] In vitro metabolism of exemestane by hepatic cytochrome P450s: impact of nonsynonymous polymorphisms on formation of the active metabolite 17beta-dihydroexemestane. Pharmacol Res Perspect. 2017 Apr 27;5(3):e00314.
• [13] 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.
• [14] Characterization of the weak estrogen receptor alpha agonistic activity of exemestane. Breast Cancer Res Treat. 2009 Aug;116(3):461-70. doi: 10.1007/s10549-008-0151-x. Epub 2008 Aug 3.
• [15] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [16] Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology. 2017 Jun 15;385:48-58. doi: 10.1016/j.tox.2017.05.001. Epub 2017 May 4.
• [17] 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.
• [18] 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.
• [19] ClinicalTrials.gov (NCT00863655) Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole
• [20] ClinicalTrials.gov (NCT02077933) Study of Safety and Efficacy of Alpelisib With Everolimus or Alpelisib With Everolimus and Exemestane in Advanced Breast Cancer Patients, Renal Cell Cancer and Pancreatic Tumors
• [21] ClinicalTrials.gov (NCT02732119) Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor.