Details of the Drug Combination

General Information of Drug Combination (ID: DCVYV4M)

• Drug Combination Name: Lenalidomide + Romidepsin
• Indication: Multiple Myeloma; Status: Phase 1 [1]
• Component Drugs:
  Lenalidomide (DM6Q7U4): Small molecular drug
  Romidepsin (DMT5GNL): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lenalidomide

Disease Entry	ICD 11	Status	REF
Adult T-cell leukemia/lymphoma	N.A.	Approved	[2]
Advanced cancer	2A00-2F9Z	Approved	[2]
Complex regional pain syndrome type 1	N.A.	Approved	[2]
Hepatosplenic T-cell lymphoma	N.A.	Approved	[2]
Large granular lymphocytic leukemia	2A90.1	Approved	[2]
Leukemia	N.A.	Approved	[2]
MALT lymphoma	N.A.	Approved	[2]
Multiple myeloma	2A83	Approved	[3]
Nodal marginal zone lymphoma	2A85.0	Approved	[2]
Pain	MG30-MG3Z	Approved	[2]
Plasma cell myeloma	2A83.1	Approved	[2]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[2]
Prolymphocytic leukaemia	2A82.1	Approved	[2]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[2]
Small intestine lymphoma	N.A.	Approved	[2]
Splenic marginal zone lymphoma	N.A.	Approved	[2]
Testicular lymphoma	N.A.	Approved	[2]
Urinary bladder neoplasm	N.A.	Approved	[2]
Waldenstrom macroglobulinemia	2A85.4	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Colon cancer	2B90.Z	Investigative	[2]

Lenalidomide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tumor necrosis factor (TNF)	TTF8CQI	TNFA_HUMAN	Inhibitor	[8]

Lenalidomide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Lenalidomide Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Affects Expression	[10]
Interleukin-1 receptor type 1 (IL1R1)	OTTU8959	IL1R1_HUMAN	Decreases Expression	[11]
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[11]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)	OTDS2EAR	TNR1B_HUMAN	Decreases Expression	[11]
Fibroblast growth factor receptor 2 (FGFR2)	OTLOPACK	FGFR2_HUMAN	Decreases Expression	[10]
Fibroblast growth factor receptor 3 (FGFR3)	OTSAXDIL	FGFR3_HUMAN	Decreases Expression	[10]
Proteinase-activated receptor 1 (F2R)	OT4WVWBO	PAR1_HUMAN	Decreases Expression	[11]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Decreases Expression	[11]
Interleukin-6 receptor subunit beta (IL6ST)	OT1N9C70	IL6RB_HUMAN	Decreases Expression	[11]
Angiopoietin-1 receptor (TEK)	OT78YN57	TIE2_HUMAN	Decreases Expression	[11]
DNA damage-binding protein 1 (DDB1)	OTTR2L3Z	DDB1_HUMAN	Affects Binding	[12]
Sal-like protein 4 (SALL4)	OTC08PR5	SALL4_HUMAN	Affects Binding	[13]
Protein cereblon (CRBN)	OTXH9MDC	CRBN_HUMAN	Increases Response To Substance	[14]

Indication(s) of Romidepsin

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[5]
Gastrin-producing neuroendocrine tumor	N.A.	Approved	[6]
Glucagonoma	N.A.	Approved	[6]
Insulinoma	2C10.1	Approved	[6]
Lung carcinoid tumor	N.A.	Approved	[6]
Melanoma	2C30	Approved	[6]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[6]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[6]
Urethral cancer	2C93	Approved	[6]
Peripheral T-cell lymphoma	2A90.C	Phase 3	[7]
Renal cell carcinoma	2C90	Phase 3	[5]

Romidepsin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histone deacetylase 1 (HDAC1)	TT6R7JZ	HDAC1_HUMAN	Inhibitor	[17]

Romidepsin Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[18]

Romidepsin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[21]

Romidepsin Interacts with 41 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[22]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Expression	[23]
E3 SUMO-protein ligase CBX4 (CBX4)	OT4XVRRF	CBX4_HUMAN	Increases Expression	[24]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[25]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[26]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[27]
Serine/threonine-protein kinase 17B (STK17B)	OT4NYNO8	ST17B_HUMAN	Increases Expression	[24]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[28]
RAF proto-oncogene serine/threonine-protein kinase (RAF1)	OT51LSFO	RAF1_HUMAN	Decreases Expression	[28]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[28]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[28]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[29]
Clusterin (CLU)	OTQGG0JM	CLUS_HUMAN	Increases Expression	[24]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[28]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[16]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[24]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[29]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[28]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[29]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[16]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[30]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Decreases Phosphorylation	[16]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[24]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[31]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[28]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[29]
Friend leukemia integration 1 transcription factor (FLI1)	OT0EV3LX	FLI1_HUMAN	Decreases Expression	[32]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Decreases Expression	[32]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[16]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Increases Expression	[30]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[24]
Spectrin alpha chain, non-erythrocytic 1 (SPTAN1)	OT6VY3A3	SPTN1_HUMAN	Increases Expression	[24]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Expression	[33]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[30]
Histone H3.1t (H3-4)	OTY6ITYF	H31T_HUMAN	Increases Acetylation	[33]
Sodium/iodide cotransporter (SLC5A5)	OTU7E9G7	SC5A5_HUMAN	Increases Expression	[34]
Mitogen-activated protein kinase kinase kinase 3 (MAP3K3)	OT53LJGW	M3K3_HUMAN	Increases Expression	[24]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Affects Metabolism	[35]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Response To Substance	[36]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Response To Substance	[29]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult Nasal Type Extranodal NK/T-cell Lymphoma	DC9Q0YM	N. A.	Phase 2	[37]
Invasive ductal carcinoma	DC1A03H	BT-549	Investigative	[38]
Adenocarcinoma	DCUDZCU	A549	Investigative	[39]
Lung adenocarcinoma	DC0RN0G	EKVX	Investigative	[39]
Lung adenocarcinoma	DC8KPAK	NCI-H522	Investigative	[39]
Malignant melanoma	DCEPNMK	LOX IMVI	Investigative	[39]
Prostate carcinoma	DC1K15G	PC-3	Investigative	[39]

References

• [1] ClinicalTrials.gov (NCT01755975) Romidepsin in Combination With Lenalidomide in Adults With Relapsed or Refractory Lymphomas and Myeloma
• [2] Lenalidomide 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: 7331).
• [4] Low-dose Lenalidomide for Non-severe COVID-19 Treatment Trial (GETAFE)
• [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: 7006).
• [6] Romidepsin FDA Label
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007351.
• [9] DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. (ID: DB00480)
• [10] Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity. Chem Res Toxicol. 2019 Apr 15;32(4):589-602. doi: 10.1021/acs.chemrestox.8b00286. Epub 2019 Mar 15.
• [11] Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005 Apr 15;105(8):3286-94. doi: 10.1182/blood-2004-06-2101. Epub 2004 Dec 23.
• [12] Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014 Sep;21(9):803-9. doi: 10.1038/nsmb.2874. Epub 2014 Aug 10.
• [13] Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome. Elife. 2018 Aug 1;7:e38430. doi: 10.7554/eLife.38430.
• [14] A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi: 10.1097/PAI.0000000000000246.
• [15] Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. Fertil Steril. 2011 Apr;95(5):1579-83. doi: 10.1016/j.fertnstert.2010.12.058. Epub 2011 Feb 4.
• [16] Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
• [17] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [18] Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
• [19] A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol. 2011 May;13(5):509-16.
• [20] Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
• [21] FDA Label of Romidepsin. The 2020 official website of the U.S. Food and Drug Administration.
• [22] Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005 Jul;314(1):467-75. doi: 10.1124/jpet.105.083956. Epub 2005 Apr 15.
• [23] Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006 Nov;26(22):8572-85.
• [24] 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun. 2006 Dec 15;351(2):455-61. doi: 10.1016/j.bbrc.2006.10.055. Epub 2006 Oct 18.
• [25] Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006 Jul 15;66(14):7317-25. doi: 10.1158/0008-5472.CAN-06-0680.
• [26] Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. Int J Cancer. 2004 Jun 10;110(2):301-8. doi: 10.1002/ijc.20117.
• [27] A sequential treatment of depsipeptide followed by 5-azacytidine enhances Gadd45beta expression in hepatocellular carcinoma cells. Anticancer Res. 2007 Nov-Dec;27(6B):3783-9.
• [28] Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Clin Cancer Res. 2004 Mar 1;10(5):1813-25. doi: 10.1158/1078-0432.ccr-0901-3.
• [29] Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res. 2008 Jan 15;14(2):549-58. doi: 10.1158/1078-0432.CCR-07-1934.
• [30] Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras. Oncotarget. 2016 Oct 25;7(43):69804-69815. doi: 10.18632/oncotarget.12001.
• [31] Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood. 2006 Feb 15;107(4):1546-54. doi: 10.1182/blood-2004-10-4126. Epub 2005 Oct 13.
• [32] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer. 2005 Sep 20;116(5):784-92. doi: 10.1002/ijc.21069.
• [33] Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol. 2005 Aug;174(2):747-52. doi: 10.1097/01.ju.0000164723.20555.e6.
• [34] Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer. 2006 Sep;13(3):797-826. doi: 10.1677/erc.1.01143.
• [35] Identification of cytochrome P450 enzymes involved in the metabolism of FK228, a potent histone deacetylase inhibitor, in human liver microsomes. Biol Pharm Bull. 2005 Jan;28(1):124-9.
• [36] Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells. Int J Cancer. 2006 Jan 1;118(1):90-7. doi: 10.1002/ijc.21297.
• [37] ClinicalTrials.gov (NCT02232516) Romidepsin and Lenalidomide in Treating Patients With Previously Untreated Peripheral T-Cell Lymphoma
• [38] 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.
• [39] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.