Details of the Drug Combination

General Information of Drug Combination (ID: DCX0RQ4)

• Drug Combination Name: Buparlisib + Letrozole
• Indication: Metastatic Breast Cancer; Status: Phase 1 [1]
• Component Drugs:
  Buparlisib (DM1WEHC): Small molecular drug
  Letrozole (DMH07Y3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Buparlisib

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

Buparlisib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase beta (PIK3CB)	TTTHBCA	PK3CB_HUMAN	Inhibitor	[6]
PI3-kinase delta (PIK3CD)	TTGBPJE	PK3CD_HUMAN	Inhibitor	[6]
PI3-kinase alpha (PIK3CA)	TTEUNMR	PK3CA_HUMAN	Inhibitor	[6]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[6]

Buparlisib Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Telomerase reverse transcriptase (TERT)	OT085VVA	TERT_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[7]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[5]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[8]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Increases Phosphorylation	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[5]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[8]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[9]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[5]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[5]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Decreases Expression	[5]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Response To Substance	[10]

Indication(s) of Letrozole

Disease Entry	ICD 11	Status	REF
Estrogen-receptor positive breast cancer	N.A.	Approved	[3]
Hormonally-responsive breast cancer	2C60-2C65	Approved	[4]

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
Advanced or Metastatic Breast Cancer	DC35L9F	N. A.	Phase 1	[25]

References

• [1] ClinicalTrials.gov (NCT01248494) PhIb BKM120 or BEZ235+Endocrine Treatment in Post-Menopausal Patients With Hormone Receptor + Metastatic Breast Cancer
• [2] 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: 7878).
• [3] Letrozole 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: 5209).
• [5] Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120. Eur J Pharmacol. 2018 Dec 15;841:10-18. doi: 10.1016/j.ejphar.2018.10.007. Epub 2018 Oct 11.
• [6] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [7] Inhibition of PI3K pathway using BKM120 intensified the chemo-sensitivity of breast cancer cells to arsenic trioxide (ATO). Int J Biochem Cell Biol. 2019 Nov;116:105615. doi: 10.1016/j.biocel.2019.105615. Epub 2019 Sep 17.
• [8] Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett. 2014 Jun 1;347(2):204-11. doi: 10.1016/j.canlet.2014.02.018. Epub 2014 Feb 24.
• [9] The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer. 2013 Jun 1;132(11):2682-93. doi: 10.1002/ijc.27935. Epub 2012 Dec 4.
• [10] Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol Cancer Ther. 2012 Aug;11(8):1747-57. doi: 10.1158/1535-7163.MCT-11-1021. Epub 2012 May 31.
• [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 (NCT02154776) Dose Escalation Study of LEE011 in Combination With Buparlisib and Letrozole in HR+, HER2-negative Post-menopausal Women With Advanced Breast Cancer.