Details of the Drug Combination

General Information of Drug Combination (ID: DC4A0IC)

• Drug Combination Name: Olaparib + Trabectedin
• Indication: Soft Tissue Sarcoma; Status: Phase 1 [1]
• Component Drugs:
  Olaparib (DM8QB1D): Small molecular drug
  Trabectedin (DMG3Y89): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Olaparib

Disease Entry	ICD 11	Status	REF
Ovarian cancer	2C73	Approved	[2]
Pancreatic cancer	2C10	Phase 3	[3]
Prostate cancer	2C82.0	Phase 3	[3]

Olaparib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Poly [ADP-ribose] polymerase (PARP)	TTEBCY8	NOUNIPROTAC	Modulator	[6]

Olaparib Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Olaparib Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]

Olaparib Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Phosphorylation	[9]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[9]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[9]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Phosphorylation	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Activity	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[9]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[11]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[11]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[9]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[11]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[11]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[11]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Increases Expression	[12]
Bromodomain-containing protein 4 (BRD4)	OT2Y2TCW	BRD4_HUMAN	Affects Response To Substance	[11]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Affects Response To Substance	[13]
DNA mismatch repair protein Msh3 (MSH3)	OTD3YPVL	MSH3_HUMAN	Decreases Response To Substance	[14]
Fumarate hydratase, mitochondrial (FH)	OTEQWU6Q	FUMH_HUMAN	Increases Response To Substance	[15]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Affects Response To Substance	[13]
Succinate dehydrogenase iron-sulfur subunit, mitochondrial (SDHB)	OTRE1M1T	SDHB_HUMAN	Increases Response To Substance	[15]
Ubiquitin carboxyl-terminal hydrolase BAP1 (BAP1)	OTS8G0EN	BAP1_HUMAN	Increases Response To Substance	[16]

Indication(s) of Trabectedin

Disease Entry	ICD 11	Status	REF
Leiomyosarcoma	2B58	Approved	[4]
Liposarcoma	2B59	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Approved	[5]
Ovarian cancer	2C73	Phase 3	[3]

Trabectedin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[18]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[19]

Trabectedin Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[20]
Transferrin receptor protein 1 (TFRC)	OT8ZPBDL	TFR1_HUMAN	Increases Expression	[21]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[20]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[20]
Cytoplasmic aconitate hydratase (ACO1)	OT2VUR7L	ACOHC_HUMAN	Increases Expression	[21]
Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4)	OTRAFFX2	GPX4_HUMAN	Decreases Expression	[21]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Increases Expression	[20]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[21]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[21]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[21]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Response To Substance	[22]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Cancers With DNA Repair-Deficiency	DC25P2Q	N. A.	Phase 2	[23]

References

• [1] ClinicalTrials.gov (NCT02398058) Trabectedin Plus Olaparib in Metastatic or Advanced Sarcomas (TOMAS)
• [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: 7519).
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Trabectedin 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: 2774).
• [6] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [7] Overexpressed ABCB1 Induces Olaparib-Taxane Cross-Resistance in Advanced Prostate Cancer. Transl Oncol. 2019 May 7;12(7):871-878.
• [8] Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells. Radiother Oncol. 2015 Sep;116(3):358-65.
• [9] PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. PLoS One. 2014 Dec 22;9(12):e114583. doi: 10.1371/journal.pone.0114583. eCollection 2014.
• [10] Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors. J Med Chem. 2017 Feb 23;60(4):1262-1271. doi: 10.1021/acs.jmedchem.6b00990. Epub 2016 Dec 21.
• [11] The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer. Gynecol Oncol. 2018 Jun;149(3):575-584. doi: 10.1016/j.ygyno.2018.03.049. Epub 2018 Mar 20.
• [12] Iron overload inhibits cell proliferation and promotes autophagy via PARP1/SIRT1 signaling in endometriosis and adenomyosis. Toxicology. 2022 Jan 15;465:153050. doi: 10.1016/j.tox.2021.153050. Epub 2021 Nov 23.
• [13] Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014.
• [14] MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor. J Biol Chem. 2011 Apr 8;286(14):12157-65. doi: 10.1074/jbc.M110.198804. Epub 2011 Feb 1.
• [15] Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 2018 Aug;50(8):1086-1092. doi: 10.1038/s41588-018-0170-4. Epub 2018 Jul 16.
• [16] BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012 Jun 10;44(7):751-9. doi: 10.1038/ng.2323.
• [17] ZNF93 increases resistance to ET-743 (Trabectedin; Yondelis) and PM00104 (Zalypsis) in human cancer cell lines. PLoS One. 2009 Sep 9;4(9):e6967. doi: 10.1371/journal.pone.0006967.
• [18] In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug. Invest New Drugs. 2006 Jan;24(1):3-14.
• [19] 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.
• [20] Selective effects of the anticancer drug Yondelis (ET-743) on cell-cycle promoters. Mol Pharmacol. 2005 Nov;68(5):1496-503. doi: 10.1124/mol.105.013615. Epub 2005 Jun 16.
• [21] Trabectedin induces ferroptosis via regulation of HIF-1/IRP1/TFR1 and Keap1/Nrf2/GPX4 axis in non-small cell lung cancer cells. Chem Biol Interact. 2023 Jan 5;369:110262. doi: 10.1016/j.cbi.2022.110262. Epub 2022 Nov 14.
• [22] The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary. Clin Cancer Res. 2011 Jul 1;17(13):4462-73. doi: 10.1158/1078-0432.CCR-10-2987. Epub 2011 May 27.
• [23] ClinicalTrials.gov (NCT03127215) Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors