Details of the Drug Combination

General Information of Drug Combination (ID: DCNQWSH)

• Drug Combination Name: Regorafenib + Capecitabine
• Indication: Rectal Cancer; Status: Phase 1 [1]
• Component Drugs:
  Regorafenib (DMHSY1I): Small molecular drug
  Capecitabine (DMTS85L): 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 Capecitabine

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[4]
Colon adenocarcinoma	N.A.	Approved	[4]
Colorectal cancer	2B91.Z	Approved	[5]
Metastasis from malignant tumor of colon	N.A.	Approved	[4]
Rectal adenocarcinoma	2B92	Approved	[4]
Breast cancer	2C60-2C65	Phase 3	[5]
Colon cancer	2B90.Z	Investigative	[4]
Gastric cancer	2B72	Investigative	[4]

Capecitabine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[15]

Capecitabine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytidine aminohydrolase (CDA)	DEKEDRC	CDD_HUMAN	Metabolism	[16]
Thymidine phosphorylase (TYMP)	DE4HCYL	TYPH_HUMAN	Metabolism	[17]

Capecitabine Interacts with 65 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Dihydropyrimidine dehydrogenase (DPYD)	OTWRF2NR	DPYD_HUMAN	Increases Expression	[18]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[19]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Expression	[19]
C-C motif chemokine 21 (CCL21)	OT7DOXEM	CCL21_HUMAN	Decreases Expression	[13]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Decreases Expression	[13]
Aquaporin-8 (AQP8)	OT99JKME	AQP8_HUMAN	Increases Expression	[13]
Complement C3 (C3)	OTCH5GS0	CO3_HUMAN	Decreases Expression	[13]
HLA class II histocompatibility antigen, DQ alpha 1 chain (HLA-DQA1)	OTC6GISG	DQA1_HUMAN	Decreases Expression	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[20]
B-lymphocyte antigen CD20 (MS4A1)	OTZTVUBX	CD20_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 4immunitygroup A member 1 (NR4A1)	OTGP6GA4	NR4A1_HUMAN	Decreases Expression	[13]
40-kDa huntingtin-associated protein (F8A1)	OTXTQ59R	HAP40_HUMAN	Decreases Expression	[13]
Chloride anion exchanger (SLC26A3)	OTBNK2U2	S26A3_HUMAN	Increases Expression	[13]
Nuclear receptor subfamily 4 group A member 2 (NR4A2)	OT3F9IR2	NR4A2_HUMAN	Decreases Expression	[13]
Potassium-transporting ATPase alpha chain 2 (ATP12A)	OTSQSKEK	AT12A_HUMAN	Increases Expression	[13]
Serine/threonine-protein kinase SIK1 (SIK1)	OT6FCHME	SIK1_HUMAN	Decreases Expression	[13]
Hemoglobin subunit beta (HBB)	OT514IKQ	HBB_HUMAN	Decreases Expression	[13]
Hemoglobin subunit alpha (HBA1)	OTW2BQF4	HBA_HUMAN	Decreases Expression	[13]
Paired box protein Pax-5 (PAX5)	OTYBJJWX	PAX5_HUMAN	Decreases Expression	[13]
Endoplasmic reticulum aminopeptidase 2 (ERAP2)	OTEMENYF	ERAP2_HUMAN	Decreases Expression	[13]
Fc receptor-like A (FCRLA)	OT6MK4M1	FCRLA_HUMAN	Decreases Expression	[13]
Leucine-rich repeat-containing protein 15 (LRRC15)	OTX7JL8H	LRC15_HUMAN	Decreases Expression	[13]
C-C motif chemokine 19 (CCL19)	OTQ2UJMH	CCL19_HUMAN	Decreases Expression	[13]
E3 ubiquitin-protein ligase TRIM31 (TRIM31)	OT7VW6RP	TRI31_HUMAN	Increases Expression	[13]
Interleukin-1 receptor type 2 (IL1R2)	OT0G7E35	IL1R2_HUMAN	Increases Response To Substance	[14]
Interleukin-17 receptor B (IL17RB)	OT0KDNSF	I17RB_HUMAN	Increases Response To Substance	[14]
Glycogen phosphorylase, brain form (PYGB)	OT2ZTJT0	PYGB_HUMAN	Increases Response To Substance	[14]
Calcium and integrin-binding protein 1 (CIB1)	OT4BVCRU	CIB1_HUMAN	Increases Response To Substance	[14]
1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)	OT5I4Y9K	PLCB_HUMAN	Increases Response To Substance	[14]
cAMP-dependent protein kinase catalytic subunit beta (PRKACB)	OT6RMDCE	KAPCB_HUMAN	Decreases Response To Substance	[14]
Claudin-3 (CLDN3)	OT71MN9S	CLD3_HUMAN	Increases Response To Substance	[14]
Replication protein A 70 kDa DNA-binding subunit (RPA1)	OT76POLP	RFA1_HUMAN	Decreases Response To Substance	[14]
Protein flightless-1 homolog (FLII)	OT7G9JG6	FLII_HUMAN	Decreases Response To Substance	[14]
Stress-induced-phosphoprotein 1 (STIP1)	OT7TXLOX	STIP1_HUMAN	Decreases Response To Substance	[14]
Ras-related protein R-Ras2 (RRAS2)	OT83NCEB	RRAS2_HUMAN	Decreases Response To Substance	[14]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Response To Substance	[14]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Response To Substance	[21]
Ras-related protein Rab-40B (RAB40B)	OTCA9ZF5	RB40B_HUMAN	Increases Response To Substance	[14]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Increases Response To Substance	[14]
Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7)	OTDNTHNR	ABCB7_HUMAN	Decreases Response To Substance	[14]
Tyrosine-protein phosphatase non-receptor type 13 (PTPN13)	OTESFZSO	PTN13_HUMAN	Decreases Response To Substance	[14]
ADP-ribosylation factor-like protein 4D (ARL4D)	OTG5I3KU	ARL4D_HUMAN	Decreases Response To Substance	[14]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Response To Substance	[14]
Inorganic pyrophosphatase (PPA1)	OTHZK1QB	IPYR_HUMAN	Increases Response To Substance	[14]
Polycystin-2 (PKD2)	OTIXBU8H	PKD2_HUMAN	Decreases Response To Substance	[14]
Protein S100-P (S100P)	OTJCXNJG	S100P_HUMAN	Increases Response To Substance	[14]
Transcriptional activator Myb (MYB)	OTJH64IV	MYB_HUMAN	Increases Response To Substance	[14]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1)	OTJISZOX	PLCE1_HUMAN	Increases Response To Substance	[14]
Plakophilin-2 (PKP2)	OTJOVF68	PKP2_HUMAN	Increases Response To Substance	[14]
Transcriptional enhancer factor TEF-1 (TEAD1)	OTK6971C	TEAD1_HUMAN	Decreases Response To Substance	[14]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Response To Substance	[14]
Myelin regulatory factor (MYRF)	OTKF6AEB	MYRF_HUMAN	Increases Response To Substance	[14]
Galectin-4 (LGALS4)	OTKQCG0H	LEG4_HUMAN	Increases Response To Substance	[14]
Four and a half LIM domains protein 1 (FHL1)	OTN535SU	FHL1_HUMAN	Decreases Response To Substance	[14]
Hepatoma-derived growth factor-related protein 3 (HDGFL3)	OTNN7WYH	HDGR3_HUMAN	Decreases Response To Substance	[14]
E3 ubiquitin-protein ligase TRIM15 (TRIM15)	OTNYAKP6	TRI15_HUMAN	Increases Response To Substance	[14]
Dermatan-sulfate epimerase (DSE)	OTQ108VJ	DSE_HUMAN	Decreases Response To Substance	[14]
Anterior gradient protein 2 homolog (AGR2)	OTRRZT7W	AGR2_HUMAN	Increases Response To Substance	[14]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Increases Response To Substance	[14]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Decreases Response To Substance	[14]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Response To Substance	[14]
3-ketoacyl-CoA thiolase, peroxisomal (ACAA1)	OTVKRET0	THIK_HUMAN	Increases Response To Substance	[14]
Tissue alpha-L-fucosidase (FUCA1)	OTW71IK4	FUCO_HUMAN	Increases Response To Substance	[14]
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Decreases Response To Substance	[14]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Increases Response To Substance	[14]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Pancreatic Cancer	DCZEKYJ	N. A.	Phase 2	[22]

References

• [1] ClinicalTrials.gov (NCT02910843) Neoadjuvant Treatment With Regorafenib and Capecitabine Combined With Radiotherapy in Locally Advanced Rectal Cancer
• [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] Capecitabine 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: 6799).
• [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] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [14] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [15] UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res. 2005 Feb 1;11(3):1226-36.
• [16] Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889. Int J Cancer. 2003 Sep 20;106(5):799-805.
• [17] Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. Mol Cancer Ther. 2002 Oct;1(12):1139-45.
• [18] DPD is a molecular determinant of capecitabine efficacy in colorectal cancer. Int J Oncol. 2007 Aug;31(2):413-8.
• [19] Effects of capecitabine and vinorelbine on cell proliferation, metabolism and COX2 and p16 expression in breast cancer cell lines and solid tumour tissues. Biomed Pharmacother. 2007 Oct;61(9):596-600.
• [20] P38 MAPK, NF-B, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression. Chem Res Toxicol. 2022 Mar 21;35(3):422-430. doi: 10.1021/acs.chemrestox.1c00317. Epub 2022 Feb 11.
• [21] A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression. Curr Drug Metab. 2008 May;9(4):336-43. doi: 10.2174/138920008784220646.
• [22] ClinicalTrials.gov (NCT02955940) An Open-Label Study to Enable Continued Treatment Access for Subjects Previously Enrolled in Studies of Ruxolitinib