General Information of Drug Combination (ID: DCHGDDP)

Drug Combination Name
Lapatinib Letrozole
Indication
Disease Entry Status REF
Neoplasms, Breast Phase 1 [1]
Component Drugs Lapatinib   DM3BH1Y Letrozole   DMH07Y3
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Lapatinib
Disease Entry ICD 11 Status REF
Breast cancer 2C60-2C65 Approved [2]
Gastroesophageal junction adenocarcinoma 2B71 Approved [3]
Melanoma 2C30 Approved [3]
Lapatinib Interacts with 3 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Erbb2 tyrosine kinase receptor (HER2) TT6EO5L ERBB2_HUMAN Inhibitor [7]
Epidermal growth factor receptor (EGFR) TTGKNB4 EGFR_HUMAN Inhibitor [7]
Eukaryotic elongation factor 2 kinase (eEF-2K) TT1QFLA EF2K_HUMAN Inhibitor [8]
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Lapatinib Interacts with 2 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [9]
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [10]
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Lapatinib Interacts with 4 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [11]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [12]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [11]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Metabolism [12]
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Lapatinib Interacts with 36 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Decreases Activity [13]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [14]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [15]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [15]
NAD(P)H dehydrogenase 1 (NQO1) OTZGGIVK NQO1_HUMAN Increases Expression [15]
Nuclear factor erythroid 2-related factor 2 (NFE2L2) OT0HENJ5 NF2L2_HUMAN Increases Activity [15]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [16]
Estrogen receptor (ESR1) OTKLU61J ESR1_HUMAN Decreases Activity [13]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [17]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [18]
DNA topoisomerase 1 (TOP1) OT51O0CF TOP1_HUMAN Decreases Expression [19]
DNA topoisomerase 2-alpha (TOP2A) OT6LPS08 TOP2A_HUMAN Decreases Expression [19]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Expression [19]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Decreases Expression [17]
Phosphatidylcholine translocator ABCB4 (ABCB4) OTE6PY83 MDR3_HUMAN Decreases Activity [20]
Receptor tyrosine-protein kinase erbB-3 (ERBB3) OTRSST0A ERBB3_HUMAN Decreases Activity [21]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases Secretion [22]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [13]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Activity [17]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Activity [17]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Activity [13]
DNA replication licensing factor MCM7 (MCM7) OT6FXC6K MCM7_HUMAN Decreases Expression [17]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [19]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [13]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [19]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [19]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [18]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [23]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Decreases Response To Substance [24]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) OTC6GISG DQA1_HUMAN Increases ADR [25]
Zinc finger protein SNAI1 (SNAI1) OTDPYAMC SNAI1_HUMAN Decreases Response To Substance [26]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Metabolism [19]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Increases Metabolism [19]
Transforming growth factor beta-1 proprotein (TGFB1) OTV5XHVH TGFB1_HUMAN Decreases Response To Substance [26]
Tenascin-X (TNXB) OTVBWAV5 TENX_HUMAN Increases ADR [25]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1) OTVVI3UI DQB1_HUMAN Increases ADR [25]
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⏷ Show the Full List of 36 DOT(s)
Indication(s) of Letrozole
Disease Entry ICD 11 Status REF
Estrogen-receptor positive breast cancer N.A. Approved [4]
Hormonally-responsive breast cancer 2C60-2C65 Approved [5]
Letrozole Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) TTSZLWK CP19A_HUMAN Inhibitor [27]
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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 [28]
Aromatase (CYP19A1) DEQX145 CP19A_HUMAN Metabolism [29]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [30]
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Letrozole Interacts with 18 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Aromatase (CYP19A1) OTZ6XF74 CP19A_HUMAN Decreases Activity [31]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Oxidation [32]
Cytochrome P450 2A6 (CYP2A6) OT52TWG3 CP2A6_HUMAN Increases Oxidation [32]
Adenylate kinase isoenzyme 1 (AK1) OT614AR3 KAD1_HUMAN Increases ADR [33]
Dickkopf-related protein 1 (DKK1) OTRDLUSP DKK1_HUMAN Increases Expression [34]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Increases Expression [35]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Increases Expression [35]
Progesterone receptor (PGR) OT0FZ3QE PRGR_HUMAN Decreases Expression [36]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Increases Expression [34]
Gap junction alpha-1 protein (GJA1) OTT94MKL CXA1_HUMAN Decreases Expression [37]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [38]
G1/S-specific cyclin-D2 (CCND2) OTDULQF9 CCND2_HUMAN Decreases Expression [38]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [39]
Leukemia inhibitory factor receptor (LIFR) OT36W9O5 LIFR_HUMAN Increases Expression [34]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [36]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [38]
Lanosterol 14-alpha demethylase (CYP51A1) OTAYHG9C CP51A_HUMAN Decreases Activity [40]
Fibroblast growth factor 22 (FGF22) OTVIX6J0 FGF22_HUMAN Increases Expression [34]
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⏷ Show the Full List of 18 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Breast Neoplasms DCKK4B7 N. A. Phase 1 [41]
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References

1 ClinicalTrials.gov (NCT00422903) Letrozole In Combination With Lapatinib In Neoadjuvant Treatment Of Early 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: 5692).
3 Lapatinib FDA Label
4 Letrozole FDA Label
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: 5209).
6 UGT-dependent regioselective glucuronidation of ursodeoxycholic acid and obeticholic acid and selective transport of the consequent acyl glucuronides by OATP1B1 and 1B3. Chem Biol Interact. 2019 Sep 1;310:108745. doi: 10.1016/j.cbi.2019.108745. Epub 2019 Jul 9.
7 Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009 Mar;153(1):13-7.
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9 Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
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11 Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703.
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13 The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 2005 Jan 1;65(1):18-25.
14 Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
15 P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem Res Toxicol. 2016 May 16;29(5):784-96.
16 Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells. Oncogene. 2005 Sep 15;24(41):6213-21. doi: 10.1038/sj.onc.1208774.
17 CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. 2014 Jul;5(7-8):261-72. doi: 10.18632/genesandcancer.24.
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21 Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res. 2009 Jun 15;15(12):4147-56. doi: 10.1158/1078-0432.CCR-08-2814. Epub 2009 Jun 9.
22 Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
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24 The K-Ras effector p38 MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation. J Biol Chem. 2017 Sep 8;292(36):15070-15079. doi: 10.1074/jbc.M117.779488. Epub 2017 Jul 24.
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27 Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
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29 Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
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33 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.
34 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.
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37 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.
38 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.
39 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.
40 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.
41 ClinicalTrials.gov (NCT00073528) Study Comparing Lapatinib (GW572016) And Letrozole Versus Letrozole In Subjects With Advanced Or Metastatic Breast Cancer