Details of the Drug Combination

General Information of Drug Combination (ID: DCEV54D)

• Drug Combination Name: Trametinib + Dabrafenib
• Indication: Cancer; Status: Phase 1 [1]
• Component Drugs:
  Trametinib (DM2JGQ3): Small molecular drug
  Dabrafenib (DMX6OE3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Trametinib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[2]
Metastatic melanoma	2E2Z	Approved	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Trametinib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MAPK/ERK kinase kinase (MAP3K)	TTROQ37	NOUNIPROTAC	Modulator	[6]
HUMAN ERK activator kinase 1 (MEK1)	TTAW3TO	MP2K1_HUMAN	Inhibitor	[4]
HUMAN ERK activator kinase 2 (MEK2)	TTWX403	MP2K2_HUMAN	Inhibitor	[4]

Trametinib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[7]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[7]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[7]
Tumor necrosis factor receptor superfamily member 16 (NGFR)	OTPKSM49	TNR16_HUMAN	Increases Expression	[8]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[7]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[7]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[7]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[9]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[8]
Guanine nucleotide-binding protein subunit alpha-11 (GNA11)	OT0K99TO	GNA11_HUMAN	Increases Response To Substance	[7]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Decreases Response To Substance	[10]
Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ)	OTOODWTU	GNAQ_HUMAN	Increases Response To Substance	[7]

Indication(s) of Dabrafenib

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[5]

Dabrafenib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase B-raf (BRAF)	TTWCGQT	BRAF_HUMAN	Inhibitor	[11]

Dabrafenib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]

Dabrafenib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[14]

Dabrafenib Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[15]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[15]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[15]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[15]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[15]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Activity	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[16]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[15]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Increases Expression	[15]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Decreases Cleavage	[17]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Affects Response To Substance	[18]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Increases Response To Substance	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Melanoma	DCXQC9Q	N. A.	Approved	[20]
Glioma	DCGYK2H	N. A.	Phase 1	[21]
Non-small-cell lung cancer	DCI71OM	N. A.	Phase 1	[22]
Melanoma	DCRRRIO	N. A.	Phase 1	[23]

References

• [1] ClinicalTrials.gov (NCT01336634) Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung 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: 6495).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [7] Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. Clin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
• [8] Harnessing autophagy to overcome mitogen-activated protein kinase kinase inhibitor-induced resistance in metastatic melanoma. Br J Dermatol. 2019 Feb;180(2):346-356. doi: 10.1111/bjd.17333. Epub 2018 Nov 25.
• [9] Physapubescin B enhances the sensitivity of gastric cancer cells to trametinib by inhibiting the STAT3 signaling pathway. Toxicol Appl Pharmacol. 2020 Dec 1;408:115273. doi: 10.1016/j.taap.2020.115273. Epub 2020 Oct 6.
• [10] Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2018 Sep;65(9):e27237. doi: 10.1002/pbc.27237. Epub 2018 May 16.
• [11] Clinical pipeline report, company report or official report of GlaxoSmithKline (2011).
• [12] Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64.
• [13] Physiologically based pharmacokinetic modeling to identify physiological and molecular characteristics driving variability in drug exposure. Clin Pharmacol Ther. 2018 Dec;104(6):1219-1228.
• [14] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [15] Dabrafenib inhibits ABCG2 and cytochrome P450 isoenzymes; potential implications for combination anticancer therapy. Toxicol Appl Pharmacol. 2022 Jan 1;434:115797. doi: 10.1016/j.taap.2021.115797. Epub 2021 Nov 13.
• [16] Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells. Toxicol In Vitro. 2020 Jun;65:104777. doi: 10.1016/j.tiv.2020.104777. Epub 2020 Jan 18.
• [17] Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy. Nat Commun. 2018 Jun 27;9(1):2500. doi: 10.1038/s41467-018-04664-0.
• [18] Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Sci Rep. 2016 May 25;6:26803. doi: 10.1038/srep26803.
• [19] Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours. Br J Cancer. 2016 Mar 15;114(6):669-79. doi: 10.1038/bjc.2016.40.
• [20] Clinical pipeline report, company report or official report of novartis.
• [21] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [22] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [23] ClinicalTrials.gov (NCT03754179) Dabrafenib/Trametinib/Hydroxychloroquine for Advanced Pretreated BRAF V600 Mutant Melanoma