Details of the Drug Combination

General Information of Drug Combination (ID: DCY6J0F)

• Drug Combination Name: Regorafenib + Cabozantinib
• Indication: Non-small Cell Lung Carcinoma; Status: Phase 2 [1]
• Component Drugs:
  Regorafenib (DMHSY1I): Small molecular drug
  Cabozantinib (DMIYDT4): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Regorafenib

Disease Entry	ICD 11	Status	REF
Gastrointestinal stromal tumour	2B5B	Approved	[2]
Metastasis from malignant tumor of colon	N.A.	Approved	[2]
Metastatic colorectal cancer	2B91	Approved	[3]

Regorafenib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Modulator	[7]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Modulator	[7]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[7]

Regorafenib Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[8]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[8]

Regorafenib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[11]

Regorafenib Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[6]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[12]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Activity	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[6]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[6]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Activity	[6]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[6]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[6]

Indication(s) of Cabozantinib

Disease Entry	ICD 11	Status	REF
Medullary thyroid gland carcinoma	N.A.	Approved	[4]
Thyroid cancer	2D10	Approved	[5]
Ovarian cancer	2C73	Phase 2	[5]

Cabozantinib Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Inhibitor	[13]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Inhibitor	[13]

Cabozantinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]

Cabozantinib Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Decreases Phosphorylation	[16]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[12]

References

• [1] ClinicalTrials.gov (NCT02795156) Study Assessing Activity of Molecularly Matched Targeted Therapies in Select Tumor Types Based on Genomic Alterations
• [2] Regorafenib FDA Label
• [3] 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: 5891).
• [4] Cabozantinib 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: 5887).
• [6] Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF-B-modulated tumor progression in bladder cancer in vitro and in vivo. Environ Toxicol. 2019 Jun;34(6):679-688. doi: 10.1002/tox.22734. Epub 2019 Feb 25.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull. 2015;38(4):582-6.
• [9] Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res. 2015 Jul;32(7):2205-16.
• [10] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
• [11] FDA Label of Regorafenib. The 2020 official website of the U.S. Food and Drug Administration.
• [12] 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.
• [13] Clinical pipeline report, company report or official report of Exelixis (2011).
• [14] Practical management of adverse events associated with cabozantinib treatment in patients with renal-cell carcinoma. Onco Targets Ther. 2017 Oct 19;10:5053-5064.
• [15] FDA Label of Cabozantinib. The 2020 official website of the U.S. Food and Drug Administration.
• [16] ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 2019 Nov 15;383:114768. doi: 10.1016/j.taap.2019.114768. Epub 2019 Oct 19.