Details of the Drug Combination

General Information of Drug Combination (ID: DCU75S9)

• Drug Combination Name: Crizotinib + Enzalutamide
• Indication: Castration-resistant Prostate Cancer; Status: Phase 1 [1]
• Component Drugs:
  Crizotinib (DM4F29C): Small molecular drug
  Enzalutamide (DMGL19D): Small molecular drug

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	[7]
ALK tyrosine kinase receptor (ALK)	TTPMQSO	ALK_HUMAN	Modulator	[7]
Proto-oncogene c-Ros (ROS1)	TTSZ6Y3	ROS1_HUMAN	Modulator	[7]
HGF/Met signaling pathway (HGF/Met pathway)	TTKA5LP	NOUNIPROTAC	Inhibitor	[8]

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	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[10]

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	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]

Crizotinib Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[12]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Response To Substance	[5]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[4]
Epithelial cell adhesion molecule (EPCAM)	OTHBZK5X	EPCAM_HUMAN	Decreases Expression	[4]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[13]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1)	OTCO26FV	HMCS1_HUMAN	Increases Expression	[13]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[13]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[13]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)	OT6KFNMS	CAC1C_HUMAN	Decreases Activity	[13]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[5]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[5]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Decreases Secretion	[14]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[14]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Activity	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[17]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[18]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[19]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[5]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Activity	[12]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Response To Substance	[20]

Indication(s) of Enzalutamide

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[3]

Enzalutamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Androgen receptor (AR)	TTS64P2	ANDR_HUMAN	Modulator	[7]

Enzalutamide Interacts with 87 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Very long chain fatty acid elongase 7 (ELOVL7)	OT89NYVC	ELOV7_HUMAN	Decreases Expression	[21]
Bone morphogenetic protein receptor type-1B (BMPR1B)	OTGFN0OD	BMR1B_HUMAN	Decreases Expression	[21]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Decreases Expression	[21]
RNA polymerase II elongation factor ELL2 (ELL2)	OTZJRTFM	ELL2_HUMAN	Decreases Expression	[21]
Suppressor of cytokine signaling 2 (SOCS2)	OTBPNKJQ	SOCS2_HUMAN	Decreases Expression	[21]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Decreases Expression	[21]
Unconventional myosin-Ib (MYO1B)	OTGZUJ0I	MYO1B_HUMAN	Decreases Expression	[21]
Kinesin heavy chain isoform 5C (KIF5C)	OT35570Y	KIF5C_HUMAN	Decreases Expression	[21]
Transcription factor Maf (MAF)	OT1GR3IZ	MAF_HUMAN	Decreases Expression	[21]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Decreases Expression	[21]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Expression	[21]
Microtubule-associated protein 2 (MAP2)	OT6UYT3X	MTAP2_HUMAN	Decreases Expression	[21]
Plastin-2 (LCP1)	OTK61F2A	PLSL_HUMAN	Decreases Expression	[21]
Kallikrein-2 (KLK2)	OT9RE37R	KLK2_HUMAN	Decreases Expression	[21]
Phospholipase A2 group V (PLA2G5)	OTQRSKCZ	PA2G5_HUMAN	Decreases Expression	[21]
Regulator of G-protein signaling 2 (RGS2)	OT0FSRW7	RGS2_HUMAN	Decreases Expression	[21]
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Decreases Expression	[21]
Selenoprotein P (SELENOP)	OT02B8IR	SEPP1_HUMAN	Decreases Expression	[21]
AF4/FMR2 family member 3 (AFF3)	OTR0705Z	AFF3_HUMAN	Decreases Expression	[21]
Cysteine-rich secretory protein 3 (CRISP3)	OTBSWMPL	CRIS3_HUMAN	Decreases Expression	[21]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Decreases Expression	[21]
Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1)	OT1TS9M9	ACSM1_HUMAN	Decreases Expression	[21]
Ras GTPase-activating-like protein IQGAP2 (IQGAP2)	OTX2UA7P	IQGA2_HUMAN	Decreases Expression	[21]
Glycine N-methyltransferase (GNMT)	OT0O2OQO	GNMT_HUMAN	Decreases Expression	[21]
Ketimine reductase mu-crystallin (CRYM)	OTRGSR6B	CRYM_HUMAN	Decreases Expression	[21]
Manganese-dependent ADP-ribose/CDP-alcohol diphosphatase (ADPRM)	OTXE3X5J	ADPRM_HUMAN	Decreases Expression	[21]
Protein GREB1 (GREB1)	OTU6ZA26	GREB1_HUMAN	Decreases Expression	[21]
EF-hand calcium-binding domain-containing protein 12 (EFCAB12)	OT1QZJEI	EFC12_HUMAN	Decreases Expression	[21]
Rho-related GTP-binding protein RhoU (RHOU)	OTERIAD4	RHOU_HUMAN	Decreases Expression	[21]
Transient receptor potential cation channel subfamily M member 8 (TRPM8)	OT7ACGYK	TRPM8_HUMAN	Decreases Expression	[21]
Alpha-protein kinase 2 (ALPK2)	OTWZZDQ9	ALPK2_HUMAN	Decreases Expression	[21]
Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial (AADAT)	OTO68C3Y	AADAT_HUMAN	Decreases Expression	[21]
Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1)	OTBML9D9	CGAT1_HUMAN	Decreases Expression	[21]
Specifically androgen-regulated gene protein (C1ORF116)	OTPYEXDM	SARG_HUMAN	Decreases Expression	[21]
ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3)	OT4GJX9R	EDEM3_HUMAN	Decreases Expression	[21]
Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1 (ST6GALNAC1)	OT3JQD99	SIA7A_HUMAN	Decreases Expression	[21]
Teneurin-1 (TENM1)	OTSKSU4V	TEN1_HUMAN	Decreases Expression	[21]
Transmembrane and coiled-coil domain protein 3 (TMCC3)	OTAIQ6V6	TMCC3_HUMAN	Decreases Expression	[21]
E3 ubiquitin-protein ligase NEURL1B (NEURL1B)	OT3BZWO8	NEU1B_HUMAN	Affects Expression	[22]
Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)	OTOKUXUH	ADA10_HUMAN	Affects Expression	[22]
Integrin beta-1-binding protein 1 (ITGB1BP1)	OTVQFNGS	ITBP1_HUMAN	Affects Expression	[22]
Sushi domain-containing protein 5 (SUSD5)	OTIMJGDH	SUSD5_HUMAN	Affects Expression	[22]
Polycomb protein EED (EED)	OTJFHCDF	EED_HUMAN	Decreases Expression	[23]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[24]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Affects Expression	[22]
Annexin A4 (ANXA4)	OTUCRYXL	ANXA4_HUMAN	Affects Expression	[22]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Cleavage	[24]
Midkine (MDK)	OTF24HKC	MK_HUMAN	Affects Expression	[22]
Hepatocyte nuclear factor 1-beta (HNF1B)	OTSYIC3T	HNF1B_HUMAN	Affects Expression	[22]
Small ribosomal subunit protein eS19 (RPS19)	OTBKGP48	RS19_HUMAN	Affects Expression	[22]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Affects Expression	[22]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Affects Expression	[22]
Transcription factor SOX-9 (SOX9)	OTVDJFGN	SOX9_HUMAN	Affects Expression	[22]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Affects Expression	[22]
Hepatocyte nuclear factor 3-alpha (FOXA1)	OTEBY0TD	FOXA1_HUMAN	Affects Expression	[22]
Ubiquitin-ribosomal protein eS31 fusion protein (RPS27A)	OTIIGGZ2	RS27A_HUMAN	Affects Expression	[22]
Protein jagged-1 (JAG1)	OT3LGT6K	JAG1_HUMAN	Affects Expression	[22]
Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17)	OTTM6KRB	ADA17_HUMAN	Affects Expression	[22]
Neurogenic locus notch homolog protein 2 (NOTCH2)	OTQ3Y9PA	NOTC2_HUMAN	Affects Expression	[22]
Peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5)	OT404F9K	FKBP5_HUMAN	Decreases Expression	[24]
SNW domain-containing protein 1 (SNW1)	OTKWG3PS	SNW1_HUMAN	Affects Expression	[22]
Transcription factor HES-1 (HES1)	OT8P19W2	HES1_HUMAN	Affects Expression	[22]
Polycomb protein SUZ12 (SUZ12)	OT655XF8	SUZ12_HUMAN	Decreases Expression	[23]
Probable E3 ubiquitin-protein ligase DTX2 (DTX2)	OT7QLDU4	DTX2_HUMAN	Affects Expression	[22]
E3 ubiquitin-protein ligase MIB1 (MIB1)	OT5C404P	MIB1_HUMAN	Affects Expression	[22]
NF-kappa-B-activating protein (NKAP)	OT7K7I8Q	NKAP_HUMAN	Affects Expression	[22]
Probable E3 ubiquitin-protein ligase DTX3 (DTX3)	OTSUUV9N	DTX3_HUMAN	Affects Expression	[22]
Polypeptide N-acetylgalactosaminyltransferase 11 (GALNT11)	OTANT9E6	GLT11_HUMAN	Affects Expression	[22]
Gamma-secretase subunit APH-1B (APH1B)	OTQHPTGC	APH1B_HUMAN	Affects Expression	[22]
Nicastrin (NCSTN)	OT5QBTA4	NICA_HUMAN	Affects Expression	[22]
Mastermind-like protein 1 (MAML1)	OTQA4DDN	MAML1_HUMAN	Affects Expression	[22]
E3 ubiquitin-protein ligase MIB2 (MIB2)	OTJCC3HS	MIB2_HUMAN	Affects Expression	[22]
p53 apoptosis effector related to PMP-22 (PERP)	OTP0YL53	PERP_HUMAN	Affects Expression	[22]
E3 ubiquitin-protein ligase Itchy homolog (ITCH)	OTUOMKF5	ITCH_HUMAN	Affects Expression	[22]
Mastermind-like protein 3 (MAML3)	OTZFV53Z	MAML3_HUMAN	Affects Expression	[22]
Intraflagellar transport protein 74 homolog (IFT74)	OTZBFEDD	IFT74_HUMAN	Affects Expression	[22]
RNA-binding protein 15 (RBM15)	OT8ZPGWF	RBM15_HUMAN	Affects Expression	[22]
Msx2-interacting protein (SPEN)	OT37A2MD	MINT_HUMAN	Affects Expression	[22]
GDP-fucose protein O-fucosyltransferase 1 (POFUT1)	OTOBJZIT	OFUT1_HUMAN	Affects Expression	[22]
Notchless protein homolog 1 (NLE1)	OT1BV82K	NLE1_HUMAN	Affects Expression	[22]
Gamma-secretase subunit PEN-2 (PSENEN)	OTJ7M7G9	PEN2_HUMAN	Affects Expression	[22]
Protein sel-1 homolog 1 (SEL1L)	OTC0FB7T	SE1L1_HUMAN	Affects Expression	[22]
Intraflagellar transport protein 172 homolog (IFT172)	OT12DW08	IF172_HUMAN	Affects Expression	[22]
Neurogenic locus notch homolog protein 3 (NOTCH3)	OTMVVA7F	NOTC3_HUMAN	Affects Expression	[22]
Protein jagged-2 (JAG2)	OTH7KRRF	JAG2_HUMAN	Affects Expression	[22]
E3 ubiquitin-protein ligase DTX4 (DTX4)	OTGX30AO	DTX4_HUMAN	Affects Expression	[22]
Epsin-1 (EPN1)	OT4Q1NIV	EPN1_HUMAN	Affects Expression	[22]

References

• [1] ClinicalTrials.gov (NCT02207504) Crizotinib in Combination With Enzalutamide in Metastatic Castration-resistant Prostate 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: 4903).
• [3] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [4] Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
• [5] 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.
• [6] 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.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
• [9] 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.
• [10] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [11] Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [22] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [23] Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer. Toxicol Appl Pharmacol. 2020 Oct 1;404:115200. doi: 10.1016/j.taap.2020.115200. Epub 2020 Aug 14.
• [24] Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. J Biol Chem. 2020 Apr 17;295(16):5470-5483. doi: 10.1074/jbc.RA119.011385. Epub 2020 Mar 17.