Details of the Drug Combination

General Information of Drug Combination (ID: DCCA60I)

• Drug Combination Name: Crizotinib + Imatinib
• Indication: Large cell lung carcinoma; Status: Investigative [1]
• Component Drugs:
  Crizotinib (DM4F29C): Small molecular drug
  Imatinib (DM7RJXL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: NCI-H460
  Zero Interaction Potency (ZIP) Score: 7.46
  Bliss Independence Score: 13.93
  Loewe Additivity Score: 2.35
  LHighest Single Agent (HSA) Score: 12.44

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Crizotinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[2]

Crizotinib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Proto-oncogene c-Met (MET)	TTNDSF4	MET_HUMAN	Modulator	[3]
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Modulator	[3]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Modulator	[3]
HGF/Met signaling pathway (HGF/Met pathway)	TTKA5LP	NOUNIPROTAC	Inhibitor	[13]

Crizotinib Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[15]

Crizotinib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]

Crizotinib Interacts with 45 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[17]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[18]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Response To Substance	[11]
ALK tyrosine kinase receptor (ALK)	OTV3P4V8	ALK_HUMAN	Decreases Response To Substance	[19]
Prominin-1 (PROM1)	OTBHV8NX	PROM1_HUMAN	Decreases Expression	[10]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[10]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[10]
Cytidine deaminase (CDA)	OT3HXP6N	CDD_HUMAN	Decreases Expression	[10]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[20]
Acyl-CoA 6-desaturase (FADS2)	OTUX531P	FADS2_HUMAN	Increases Expression	[20]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[20]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Increases Expression	[20]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[20]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[20]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[20]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[20]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[20]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[20]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[20]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[11]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[11]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Decreases Secretion	[21]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[21]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[22]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[23]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[24]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[23]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[25]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[26]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[26]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[27]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Phosphorylation	[28]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[29]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[28]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[11]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[30]
Echinoderm microtubule-associated protein-like 4 (EML4)	OTJC45TA	EMAL4_HUMAN	Increases Mutagenesis	[26]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[18]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Decreases Response To Substance	[31]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Response To Substance	[27]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Response To Substance	[31]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Response To Substance	[19]
Proheparin-binding EGF-like growth factor (HBEGF)	OTLU00JS	HBEGF_HUMAN	Decreases Response To Substance	[27]
Protransforming growth factor alpha (TGFA)	OTPD1LL9	TGFA_HUMAN	Decreases Response To Substance	[27]

Indication(s) of Imatinib

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Approved	[3]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	N.A.	Approved	[4]
Choroidal neovascularization	9B76	Approved	[4]
Chronic eosinophilic leukemia	N.A.	Approved	[4]
Chronic myelogenous leukaemia	2A20.0	Approved	[5]
Chronic myeloid leukaemia	2A20	Approved	[6]
Dermatofibrosarcoma protuberans	N.A.	Approved	[4]
Gastrointestinal stromal tumour	2B5B	Approved	[4]
Leukemia	N.A.	Approved	[4]
Malignant peripheral nerve sheath tumor	N.A.	Approved	[4]
Myeloproliferative neoplasm	2A20	Approved	[4]
Pulmonary hypertension	BB01	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Intestinal cancer	2C0Z	Phase 3	[5]
Lung cancer	2C25.0	Phase 2	[5]
Idiopathic hypereosinophilic syndrome	N.A.	Investigative	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[8]
Scleroderma	4A42	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[8]
Systemic mastocytosis	2A21.0	Investigative	[9]

Imatinib Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mcl-1 messenger RNA (MCL-1 mRNA)	TTN6ORK	MCL1_HUMAN	.	[9]
Fusion protein Bcr-Abl (Bcr-Abl)	TTS7G69	BCR_HUMAN-ABL1_HUMAN	Inhibitor	[35]
Platelet-derived growth factor receptor (PDGFR)	TTI2WET	NOUNIPROTAC	Inhibitor	[35]
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Inhibitor	[35]
HUMAN fusion protein Bcr-Abl (Bcr-Abl)	TTE63HY	BCR_HUMAN/ABL1_HUMAN	Inhibitor	[8]

Imatinib Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[36]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[37]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[38]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[39]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[15]

Imatinib Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[40]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[41]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[42]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[43]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[44]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[45]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[46]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[42]

Imatinib Interacts with 95 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Methylation	[47]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Methylation	[47]
Cytochrome P450 3A7 (CYP3A7)	OTTCDHHM	CP3A7_HUMAN	Decreases Methylation	[47]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Methylation	[47]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[48]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[48]
Aldehyde dehydrogenase, mitochondrial (ALDH2)	OTKJ9I3N	ALDH2_HUMAN	Decreases Expression	[49]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Decreases Expression	[49]
Fructose-bisphosphate aldolase C (ALDOC)	OTEC13I5	ALDOC_HUMAN	Decreases Expression	[49]
Pyruvate dehydrogenase E1 component subunit beta, mitochondrial (PDHB)	OT2NHE5E	ODPB_HUMAN	Decreases Expression	[49]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[49]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[49]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Expression	[49]
Eukaryotic translation initiation factor 4B (EIF4B)	OTE8TXA8	IF4B_HUMAN	Decreases Expression	[49]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Expression	[49]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[49]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[49]
Hexokinase-4 (GCK)	OTR3Q0NN	HXK4_HUMAN	Decreases Expression	[49]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Expression	[49]
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA)	OT83PT85	PP2AA_HUMAN	Increases Expression	[49]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Expression	[49]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[50]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[51]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[52]
Autophagy-related protein 13 (ATG13)	OTYMHNEJ	ATG13_HUMAN	Increases Phosphorylation	[32]
Platelet-derived growth factor subunit B (PDGFB)	OTMFMFC3	PDGFB_HUMAN	Decreases Expression	[53]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[54]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[55]
Keratin, type I cytoskeletal 14 (KRT14)	OTUVZ1DW	K1C14_HUMAN	Increases Expression	[56]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[57]
Heat shock protein beta-1 (HSPB1)	OTHFZ8ED	HSPB1_HUMAN	Increases Expression	[52]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[58]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[52]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Phosphorylation	[59]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[54]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Increases Expression	[32]
Proto-oncogene tyrosine-protein kinase receptor Ret (RET)	OTLU040A	RET_HUMAN	Decreases Phosphorylation	[60]
ATP-dependent 6-phosphofructokinase, muscle type (PFKM)	OT1QY9JM	PFKAM_HUMAN	Decreases Expression	[61]
Platelet-derived growth factor receptor beta (PDGFRB)	OTYSNK9Q	PGFRB_HUMAN	Decreases Expression	[53]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[62]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[52]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[63]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[57]
Breakpoint cluster region protein (BCR)	OTCN76C1	BCR_HUMAN	Decreases Activity	[34]
Lysosome-associated membrane glycoprotein 1 (LAMP1)	OTYE92QY	LAMP1_HUMAN	Increases Expression	[32]
Ornithine decarboxylase (ODC1)	OTNDAGRR	DCOR_HUMAN	Increases Expression	[52]
Keratin, type II cytoskeletal 5 (KRT5)	OTVGI9HT	K2C5_HUMAN	Increases Expression	[56]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[24]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[64]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Expression	[53]
CCAAT/enhancer-binding protein beta (CEBPB)	OTM9MQIA	CEBPB_HUMAN	Increases Expression	[52]
Histidine decarboxylase (HDC)	OT4WA5YQ	DCHS_HUMAN	Decreases Expression	[65]
Transcription factor EB (TFEB)	OTJUJJQY	TFEB_HUMAN	Affects Localization	[32]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Decreases Expression	[66]
Insulin-like growth factor-binding protein 4 (IGFBP4)	OT2HZRBD	IBP4_HUMAN	Increases Expression	[52]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[25]
Interleukin-4 receptor subunit alpha (IL4R)	OTTXOTCW	IL4RA_HUMAN	Increases Expression	[52]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[54]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Phosphorylation	[52]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[59]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[59]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Increases Cleavage	[55]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[67]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[68]
Crk-like protein (CRKL)	OTOYSD1R	CRKL_HUMAN	Decreases Phosphorylation	[69]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Phosphorylation	[32]
Hexokinase-2 (HK2)	OTC0GCQO	HXK2_HUMAN	Decreases Expression	[61]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[32]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Expression	[52]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[67]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[63]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[70]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[62]
Forkhead box protein M1 (FOXM1)	OT5887KR	FOXM1_HUMAN	Decreases Expression	[67]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[71]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[32]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[32]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[72]
NGFI-A-binding protein 2 (NAB2)	OTG4BDF3	NAB2_HUMAN	Increases Expression	[52]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[73]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[58]
TRAF family member-associated NF-kappa-B activator (TANK)	OTZSGFIK	TANK_HUMAN	Increases Expression	[52]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[55]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[72]
Docking protein 1 (DOK1)	OTGVRLW6	DOK1_HUMAN	Decreases Phosphorylation	[74]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[32]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[75]
V-type proton ATPase subunit H (ATP6V1H)	OTX17GQ9	VATH_HUMAN	Increases Expression	[32]
Tyrosine-protein kinase ABL1 (ABL1)	OT09YVXH	ABL1_HUMAN	Increases Response To Substance	[76]
LYR motif-containing protein 9 (LYRM9)	OT1MILTK	LYRM9_HUMAN	Affects Response To Substance	[77]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Increases ADR	[78]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Response To Substance	[79]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Response To Substance	[80]
Tyrosine-protein kinase Lyn (LYN)	OTP686K2	LYN_HUMAN	Decreases Response To Substance	[69]
Serine/threonine-protein kinase PLK1 (PLK1)	OTRZX45T	PLK1_HUMAN	Increases Response To Substance	[62]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCOSU67	OVCAR3	Investigative	[1]
Astrocytoma	DC2M3GQ	U251	Investigative	[1]
Chronic myelogenous leukemia	DCYLG08	K-562	Investigative	[1]
Melanoma	DCMAGFQ	UACC-257	Investigative	[1]
Invasive ductal carcinoma	DCK6T8D	T-47D	Investigative	[81]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 4903).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Imatinib 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: 5687).
• [6] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 078340.
• [7] ClinicalTrials.gov (NCT04356495) Treatments to Decrease the Risk of Hospitalization or Death in Elderly Outpatients With Symptomatic SARS-CoV-2 Infection (COVID-19). U.S. National Institutes of Health.
• [8] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [9] Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.
• [10] Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
• [11] Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
• [12] Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.
• [13] Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
• [14] Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94.
• [15] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [16] Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
• [17] Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes. Drug Metab Dispos. 2013 Feb;41(2):343-52.
• [18] Editor's Highlight: PlacentalDisposition and Effects of Crizotinib: An Ex Vivo Study in the Isolated Dual-Side Perfused Human Cotyledon. Toxicol Sci. 2017 Jun 1;157(2):500-509. doi: 10.1093/toxsci/kfx063.
• [19] Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
• [20] Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
• [21] Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012 Nov 1;118(21):5302-9. doi: 10.1002/cncr.27450. Epub 2012 Apr 4.
• [22] Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63. doi: 10.1021/jm2007613. Epub 2011 Aug 18.
• [23] 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.
• [24] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [25] 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.
• [26] Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.
• [27] Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clin Cancer Res. 2012 Jul 1;18(13):3592-602. doi: 10.1158/1078-0432.CCR-11-2972. Epub 2012 May 2.
• [28] Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011 Dec;78(6):999-1005. doi: 10.1111/j.1747-0285.2011.01239.x. Epub 2011 Oct 31.
• [29] Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
• [30] Keratinocytes apoptosis contributes to crizotinib induced-erythroderma. Toxicol Lett. 2020 Feb 1;319:102-110. doi: 10.1016/j.toxlet.2019.11.007. Epub 2019 Nov 7.
• [31] Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. doi: 10.1158/1078-0432.CCR-11-2906. Epub 2012 Jan 10.
• [32] Imatinib disturbs lysosomal function and morphology and impairs the activity of mTORC1 in human hepatocyte cell lines. Food Chem Toxicol. 2022 Apr;162:112869. doi: 10.1016/j.fct.2022.112869. Epub 2022 Feb 16.
• [33] Insulin-like growth factor I receptor pathway inhibition by ADW742, alone or in combination with imatinib, doxorubicin, or vincristine, is a novel therapeutic approach in Ewing tumor. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3532-40. doi: 10.1158/1078-0432.CCR-05-1778.
• [34] Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation. Cancer. 2004 Sep 1;101(5):979-88. doi: 10.1002/cncr.20457.
• [35] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [36] Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
• [37] Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004 Nov 1;104(9):2940-2.
• [38] Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. Leuk Lymphoma. 2008 Apr;49(4):639-42.
• [39] Environmental and genetic factors affecting transport of imatinib by OATP1A2. Clin Pharmacol Ther. 2011 Jun;89(6):816-20.
• [40] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [41] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [42] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [43] Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879-94.
• [44] Drug Interactions Flockhart Table
• [45] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [46] Drug-drug interactions with imatinib: an observational study. Medicine (Baltimore). 2016 Oct;95(40):e5076.
• [47] Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes. Br J Pharmacol. 2010 Nov;161(5):1059-69. doi: 10.1111/j.1476-5381.2010.00946.x.
• [48] Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther. 2005 Jul;4(7):747-52.
• [49] A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3378-83.
• [50] 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.
• [51] Anti-leukemic effects of gallic acid on human leukemia K562 cells: downregulation of COX-2, inhibition of BCR/ABL kinase and NF-B inactivation. Toxicol In Vitro. 2012 Apr;26(3):396-405.
• [52] Effects of Imatinib Mesylate (Gleevec) on human islet NF-kappaB activation and chemokine production in vitro. PLoS One. 2011;6(9):e24831. doi: 10.1371/journal.pone.0024831. Epub 2011 Sep 14.
• [53] Chemosensitization by STI571 targeting the platelet-derived growth factor/platelet-derived growth factor receptor-signaling pathway in the tumor progression and angiogenesis of gastric carcinoma. Cancer. 2005 May 1;103(9):1800-9. doi: 10.1002/cncr.20973.
• [54] Imatinib mesylate, a new kid on the block for the treatment of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis?. Clin Exp Immunol. 2008 Mar;151(3):391-8. doi: 10.1111/j.1365-2249.2007.03572.x. Epub 2008 Jan 10.
• [55] Imatinib-induced hepatotoxicity via oxidative stress and activation of NLRP3 inflammasome: an in vitro and in vivo study. Arch Toxicol. 2022 Apr;96(4):1075-1087. doi: 10.1007/s00204-022-03245-x. Epub 2022 Feb 22.
• [56] Oral lichenoid eruption secondary to imatinib (Glivec). J Dermatolog Treat. 2004 Jul;15(4):253-5. doi: 10.1080/09546630410015556.
• [57] AMP-activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR-ABL protein in CML cells. Cancer Sci. 2021 Jan;112(1):194-204. doi: 10.1111/cas.14698. Epub 2020 Nov 16.
• [58] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [59] Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood. 2004 Aug 15;104(4):1094-9. doi: 10.1182/blood-2003-12-4266. Epub 2004 Apr 20.
• [60] Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clin Cancer Res. 2005 Feb 1;11(3):1336-41.
• [61] Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem Biol Interact. 2015 May 25;233:147-56. doi: 10.1016/j.cbi.2015.03.028. Epub 2015 Apr 8.
• [62] Efficacy of the polo-like kinase inhibitor rigosertib, alone or in combination with Abelson tyrosine kinase inhibitors, against break point cluster region-c-Abelson-positive leukemia cells. Oncotarget. 2015 Aug 21;6(24):20231-40. doi: 10.18632/oncotarget.4047.
• [63] Saikosaponin D disrupts platelet-derived growth factor- receptor/p38 pathway leading to mitochondrial apoptosis in human LO2 hepatocyte cells: a potential mechanism of hepatotoxicity. Chem Biol Interact. 2013 Oct 25;206(1):76-82. doi: 10.1016/j.cbi.2013.08.006. Epub 2013 Aug 28.
• [64] Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells. Cancer Res. 2010 Jan 1;70(1):150-9. doi: 10.1158/0008-5472.CAN-09-1449. Epub 2009 Dec 22.
• [65] The CML-related oncoprotein BCR/ABL induces expression of histidine decarboxylase (HDC) and the synthesis of histamine in leukemic cells. Blood. 2006 Nov 15;108(10):3538-47. doi: 10.1182/blood-2005-12-028456. Epub 2006 Jul 18.
• [66] Increased expression of fibroblast growth factor receptor 3 in CD34+ BCR-ABL+ cells from patients with chronic myeloid leukemia. Leukemia. 2003 Dec;17(12):2418-25. doi: 10.1038/sj.leu.2403152.
• [67] Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia. Clin Cancer Res. 2017 Feb 1;23(3):789-803. doi: 10.1158/1078-0432.CCR-16-0226. Epub 2016 Aug 4.
• [68] In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol. 2002 Jul;30(7):729-37. doi: 10.1016/s0301-472x(02)00836-6.
• [69] Establishment and characterization of a novel imatinib-sensitive chronic myeloid leukemia cell line MYL, and an imatinib-resistant subline MYL-R showing overexpression of Lyn. Eur J Haematol. 2007 May;78(5):417-31. doi: 10.1111/j.1600-0609.2007.00835.x.
• [70] The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Mol Pharmacol. 2001 Mar;59(3):453-61. doi: 10.1124/mol.59.3.453.
• [71] Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis. Toxicol Lett. 2022 Jul 15;365:11-23. doi: 10.1016/j.toxlet.2022.06.001. Epub 2022 Jun 6.
• [72] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.
• [73] A new strategy for the rapid identification and validation of direct toxicity targets of psoralen-induced hepatotoxicity. Toxicol Lett. 2022 Jun 15;363:11-26. doi: 10.1016/j.toxlet.2022.05.002. Epub 2022 May 18.
• [74] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 2009 May 1;69(9):3927-36. doi: 10.1158/0008-5472.CAN-08-2978. Epub 2009 Apr 14.
• [75] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [76] Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib. Clin Chem. 2004 Jul;50(7):1205-13. doi: 10.1373/clinchem.2004.031112. Epub 2004 Apr 23.
• [77] Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci. 2016 May;151(1):10-22. doi: 10.1093/toxsci/kfw032. Epub 2016 Mar 22.
• [78] 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.
• [79] Disruption of the inhibitor of apoptosis protein survivin sensitizes Bcr-abl-positive cells to STI571-induced apoptosis. Cancer Res. 2005 Sep 15;65(18):8224-32. doi: 10.1158/0008-5472.CAN-05-0303.
• [80] Epigenetic down-regulation of BIM expression is associated with reduced optimal responses to imatinib treatment in chronic myeloid leukaemia. Eur J Cancer. 2009 Jul;45(10):1877-89. doi: 10.1016/j.ejca.2009.04.005. Epub 2009 May 4.
• [81] 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.