General Information of Drug Combination (ID: DCXLBD2)

Drug Combination Name
Lapatinib MK-5108
Indication
Disease Entry Status REF
Malignant melanoma Investigative [1]
Component Drugs Lapatinib   DM3BH1Y MK-5108   DMFGYKS
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: HT144
Zero Interaction Potency (ZIP) Score: 0.47
Bliss Independence Score: 7
Loewe Additivity Score: 4.53
LHighest Single Agent (HSA) Score: 11.6

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 [6]
Epidermal growth factor receptor (EGFR) TTGKNB4 EGFR_HUMAN Inhibitor [6]
Eukaryotic elongation factor 2 kinase (eEF-2K) TT1QFLA EF2K_HUMAN Inhibitor [7]
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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 [8]
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [9]
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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 [10]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [11]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [10]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Metabolism [11]
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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 [12]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [13]
Superoxide dismutase , mitochondrial (SOD2) OTIWXGZ9 SODM_HUMAN Increases Expression [14]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [14]
NAD(P)H dehydrogenase 1 (NQO1) OTZGGIVK NQO1_HUMAN Increases Expression [14]
Nuclear factor erythroid 2-related factor 2 (NFE2L2) OT0HENJ5 NF2L2_HUMAN Increases Activity [14]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [15]
Estrogen receptor (ESR1) OTKLU61J ESR1_HUMAN Decreases Activity [12]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [16]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [17]
DNA topoisomerase 1 (TOP1) OT51O0CF TOP1_HUMAN Decreases Expression [18]
DNA topoisomerase 2-alpha (TOP2A) OT6LPS08 TOP2A_HUMAN Decreases Expression [18]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Expression [18]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Decreases Expression [16]
Phosphatidylcholine translocator ABCB4 (ABCB4) OTE6PY83 MDR3_HUMAN Decreases Activity [19]
Receptor tyrosine-protein kinase erbB-3 (ERBB3) OTRSST0A ERBB3_HUMAN Decreases Activity [20]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases Secretion [21]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [12]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Activity [16]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Activity [16]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Activity [12]
DNA replication licensing factor MCM7 (MCM7) OT6FXC6K MCM7_HUMAN Decreases Expression [16]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [18]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [12]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [18]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [18]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [17]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [22]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Decreases Response To Substance [23]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1) OTC6GISG DQA1_HUMAN Increases ADR [24]
Zinc finger protein SNAI1 (SNAI1) OTDPYAMC SNAI1_HUMAN Decreases Response To Substance [25]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Metabolism [18]
Cytochrome P450 3A7 (CYP3A7) OTTCDHHM CP3A7_HUMAN Increases Metabolism [18]
Transforming growth factor beta-1 proprotein (TGFB1) OTV5XHVH TGFB1_HUMAN Decreases Response To Substance [25]
Tenascin-X (TNXB) OTVBWAV5 TENX_HUMAN Increases ADR [24]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1) OTVVI3UI DQB1_HUMAN Increases ADR [24]
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⏷ Show the Full List of 36 DOT(s)
Indication(s) of MK-5108
Disease Entry ICD 11 Status REF
Solid tumour/cancer 2A00-2F9Z Phase 1 [4]
MK-5108 Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Aurora kinase B (AURKB) TT5LS6T AURKB_HUMAN Inhibitor [26]
Aurora kinase A (AURKA) TTPS3C0 AURKA_HUMAN Inhibitor [26]
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Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Breast and ovarian cancer syndrome DCWIP4F UWB1289 Investigative [27]
Breast and ovarian cancer syndrome DC857MR UWB1289+BRCA1 Investigative [27]
Breast carcinoma DCJ3GIX OCUBM Investigative [27]
Carcinoma DCDUNLJ EFM192B Investigative [27]
Colon adenocarcinoma DCM8K8T LOVO Investigative [27]
Colon carcinoma DCVCROF RKO Investigative [27]
Adenocarcinoma DCGBWQ7 CAOV3 Investigative [1]
Adenocarcinoma DCBUJM5 OVCAR3 Investigative [1]
Adenocarcinoma DC5JDCW A427 Investigative [1]
Adenocarcinoma DC74E5U NCIH1650 Investigative [1]
Adenocarcinoma DCCA7UO NCIH23 Investigative [1]
Adenocarcinoma DC6IYBF COLO320DM Investigative [1]
Adenocarcinoma DC1YJUD DLD1 Investigative [1]
Adenocarcinoma DCLZLZF HCT116 Investigative [1]
Adenocarcinoma DCD36I8 HT29 Investigative [1]
Amelanotic melanoma DC3JF88 A2058 Investigative [1]
Ewing sarcoma-peripheral primitive neuroectodermal tumour DC346TM ES2 Investigative [1]
Malignant melanoma DC6HQTJ A375 Investigative [1]
Malignant melanoma DCIZ5SN RPMI7951 Investigative [1]
Malignant melanoma DC2LUNB SKMEL30 Investigative [1]
Malignant melanoma DCF8N2D UACC62 Investigative [1]
Mesothelioma DC56TEL MSTO Investigative [1]
Non small cell carcinoma DCZ4ZT5 SKMES1 Investigative [1]
Ovarian endometrioid adenocarcinoma DCDIUAT A2780 Investigative [1]
Ovarian serous cystadenocarcinoma DCYFM9K SK-OV-3 Investigative [1]
Prostate carcinoma DCC9HJ7 VCAP Investigative [1]
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⏷ Show the Full List of 26 DrugCom(s)

References

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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 ClinicalTrials.gov (NCT00543387) Treatment of Participants With Advanced and/or Refractory Solid Tumors (MK-5108-001 AM4). U.S. National Institutes of Health.
5 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.
6 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.
7 Inhibition of eEF-2 kinase sensitizes human nasopharyngeal carcinoma cells to lapatinib-induced apoptosis through the Src and Erk pathways.BMC Cancer. 2016 Oct 19;16(1):813.
8 Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
9 The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos. 2008 Apr;36(4):695-701.
10 Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 2010 Oct;78(4):693-703.
11 Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
12 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.
13 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.
14 P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem Res Toxicol. 2016 May 16;29(5):784-96.
15 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.
16 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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18 The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib. Toxicol Sci. 2023 Dec 21;197(1):69-78. doi: 10.1093/toxsci/kfad099.
19 Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
20 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.
21 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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23 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.
24 HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011 Feb 20;29(6):667-73. doi: 10.1200/JCO.2010.31.3197. Epub 2011 Jan 18.
25 Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer. Int J Biochem Cell Biol. 2016 Feb;71:12-23. doi: 10.1016/j.biocel.2015.11.014. Epub 2015 Nov 28.
26 A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
27 Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.