Details of the Drug Combination

General Information of Drug Combination (ID: DC6QIZI)

• Drug Combination Name: Erlotinib + Bexarotene
• Indication: Lung Cancer; Status: Phase 1 [1]
• Component Drugs:
  Erlotinib (DMCMBHA): Small molecular drug
  Bexarotene (DMOBIKY): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[2]
Adult hepatocellular carcinoma	N.A.	Approved	[2]
Brain cancer	2A00	Approved	[2]
Esophageal disorder	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Pancreatic adenocarcinoma	N.A.	Approved	[2]
Psoriasis	EA90	Approved	[2]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Pancreatic cancer	2C10	Phase 3	[3]
Colon cancer	2B90.Z	Phase 2	[3]
Ependymoma	2A00.0Y	Investigative	[2]
Neoplastic meningitis	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]

Erlotinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[6]

Erlotinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]

Erlotinib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]

Erlotinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response	[11]

Indication(s) of Bexarotene

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[4]
Plasma cell myeloma	2A83.1	Approved	[5]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[5]
Schizoaffective disorder	6A21	Approved	[5]

Bexarotene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Retinoic acid receptor RXR-alpha (RXRA)	TT6PEUO	RXRA_HUMAN	Modulator	[13]

Bexarotene Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]

Bexarotene Interacts with 86 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[15]
Keratin, type I cytoskeletal 14 (KRT14)	OTUVZ1DW	K1C14_HUMAN	Decreases Expression	[16]
Involucrin (IVL)	OT4VPNGY	INVO_HUMAN	Decreases Expression	[16]
Keratin, type II cytoskeletal 5 (KRT5)	OTVGI9HT	K2C5_HUMAN	Decreases Expression	[16]
Protein-glutamine gamma-glutamyltransferase K (TGM1)	OTB8URRI	TGM1_HUMAN	Decreases Expression	[16]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[12]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Decreases Expression	[12]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[12]
Period circadian protein homolog 2 (PER2)	OTU2B1DJ	PER2_HUMAN	Decreases Expression	[12]
Cytochrome P450 26A1 (CYP26A1)	OTL1DFWV	CP26A_HUMAN	Increases Expression	[12]
E3 ubiquitin-protein ligase SIAH2 (SIAH2)	OTKED2XN	SIAH2_HUMAN	Decreases Expression	[12]
Integral membrane protein 2A (ITM2A)	OT590V63	ITM2A_HUMAN	Increases Expression	[12]
Transcription factor Maf (MAF)	OT1GR3IZ	MAF_HUMAN	Increases Expression	[12]
Short-chain dehydrogenase/reductase 3 (DHRS3)	OTSK1DTP	DHRS3_HUMAN	Increases Expression	[12]
PRA1 family protein 3 (ARL6IP5)	OTYZ6BEQ	PRAF3_HUMAN	Increases Expression	[12]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[12]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[12]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[12]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[12]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[12]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[12]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Decreases Expression	[12]
SPARC (SPARC)	OTPN90H0	SPRC_HUMAN	Increases Expression	[12]
Pro-cathepsin H (CTSH)	OTLFL0DG	CATH_HUMAN	Increases Expression	[12]
Retinoic acid receptor beta (RARB)	OT367U3E	RARB_HUMAN	Increases Expression	[12]
Ornithine decarboxylase (ODC1)	OTNDAGRR	DCOR_HUMAN	Decreases Expression	[12]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Decreases Expression	[12]
Integrin beta-6 (ITGB6)	OTI3DJ7U	ITB6_HUMAN	Increases Expression	[12]
Keratin, type I cytoskeletal 15 (KRT15)	OTS6WLF7	K1C15_HUMAN	Increases Expression	[12]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2)	OT6MFOWF	TGM2_HUMAN	Increases Expression	[12]
Insulin-like growth factor-binding protein 6 (IGFBP6)	OTW878VI	IBP6_HUMAN	Increases Expression	[12]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Decreases Expression	[12]
Ephrin type-A receptor 2 (EPHA2)	OTI6QNX2	EPHA2_HUMAN	Decreases Expression	[12]
Transmembrane 4 L6 family member 1 (TM4SF1)	OTY0ECQN	T4S1_HUMAN	Increases Expression	[12]
High affinity cationic amino acid transporter 1 (SLC7A1)	OTR2ZVA8	CTR1_HUMAN	Decreases Expression	[12]
Cystathionine gamma-lyase (CTH)	OTC90LA0	CGL_HUMAN	Decreases Expression	[12]
Interleukin-15 (IL15)	OTQSYWQS	IL15_HUMAN	Increases Expression	[12]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[12]
Glycine--tRNA ligase (GARS1)	OT5B6R9Y	GARS_HUMAN	Decreases Expression	[12]
Eukaryotic translation initiation factor 1 (EIF1)	OTB4GZ0V	EIF1_HUMAN	Decreases Expression	[12]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[12]
CCAAT/enhancer-binding protein gamma (CEBPG)	OTGNAX3H	CEBPG_HUMAN	Decreases Expression	[12]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Decreases Expression	[12]
Serine/arginine-rich splicing factor 2 (SRSF2)	OTVDHO6U	SRSF2_HUMAN	Decreases Expression	[12]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Decreases Expression	[12]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Decreases Expression	[12]
Keratin, type I cytoskeletal 17 (KRT17)	OT6Y1DPK	K1C17_HUMAN	Decreases Expression	[12]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[12]
Early growth response protein 3 (EGR3)	OTGPJIRA	EGR3_HUMAN	Decreases Expression	[12]
Proline-rich nuclear receptor coactivator 1 (PNRC1)	OTQMLEE1	PNRC1_HUMAN	Increases Expression	[12]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2)	OTVZD4H6	BNIP2_HUMAN	Decreases Expression	[12]
Protein AF1q (MLLT11)	OTG5RVHC	AF1Q_HUMAN	Increases Expression	[12]
Krueppel-like factor 10 (KLF10)	OT4F4UGS	KLF10_HUMAN	Decreases Expression	[12]
Neuronal membrane glycoprotein M6-b (GPM6B)	OT8Q1582	GPM6B_HUMAN	Increases Expression	[12]
Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1)	OTX7MWW1	ITPR1_HUMAN	Increases Expression	[12]
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein (HERPUD1)	OT9EROL6	HERP1_HUMAN	Decreases Expression	[12]
Adipogenesis regulatory factor (ADIRF)	OTTJP8D4	ADIRF_HUMAN	Increases Expression	[12]
Dual specificity protein phosphatase 5 (DUSP5)	OTH96RA7	DUS5_HUMAN	Decreases Expression	[12]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[12]
Mothers against decapentaplegic homolog 5 (SMAD5)	OTQNSVCQ	SMAD5_HUMAN	Increases Expression	[12]
Immediate early response gene 2 protein (IER2)	OT5OY8BO	IER2_HUMAN	Decreases Expression	[12]
RNA-binding protein PNO1 (PNO1)	OT010GIS	PNO1_HUMAN	Decreases Expression	[12]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[12]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[12]
Gamma-adducin (ADD3)	OTDRSHAZ	ADDG_HUMAN	Increases Expression	[12]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Decreases Expression	[12]
Angiomotin-like protein 2 (AMOTL2)	OTRCTKV9	AMOL2_HUMAN	Decreases Expression	[12]
Lysyl oxidase homolog 2 (LOXL2)	OTRT46B5	LOXL2_HUMAN	Increases Expression	[12]
Tumor protein p73 (TP73)	OT0LUO47	P73_HUMAN	Increases Expression	[17]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[17]
Apolipoprotein A-II (APOA2)	OTQ3HGTC	APOA2_HUMAN	Increases Expression	[18]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[19]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[20]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[17]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[17]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[21]
Retinoic acid receptor RXR-beta (RXRB)	OTNPDXG2	RXRB_HUMAN	Affects Binding	[15]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[22]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Retinoic acid receptor RXR-gamma (RXRG)	OT254B09	RXRG_HUMAN	Affects Binding	[15]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Increases Expression	[23]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Decreases Expression	[22]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Activity	[17]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[24]
Sonic hedgehog protein (SHH)	OTOG2BXF	SHH_HUMAN	Increases Expression	[24]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[22]

References

• [1] ClinicalTrials.gov (NCT00411632) BATTLE Program: Tarceva and Targretin in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
• [2] Erlotinib 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: 4920).
• [4] 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: 2807).
• [5] Bexarotene FDA Label
• [6] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [7] Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7.
• [8] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [9] In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9.
• [10] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [11] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
• [12] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [14] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [15] Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor , , subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11.
• [16] Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells. Cell Growth Differ. 1996 Aug;7(8):997-1004.
• [17] Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol. 2009 Mar;160(3):519-26. doi: 10.1111/j.1365-2133.2008.08931.x. Epub 2008 Nov 25.
• [18] Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. Mol Cell Biol. 1996 Jul;16(7):3350-60. doi: 10.1128/MCB.16.7.3350.
• [19] Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch Dermatol. 2005 Mar;141(3):315-21. doi: 10.1001/archderm.141.3.315.
• [20] Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat. 2006 Mar;96(2):147-57. doi: 10.1007/s10549-005-9071-1. Epub 2005 Nov 5.
• [21] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [22] Combinations of LXR and RXR agonists induce triglyceride accumulation in human HepaRG cells in a synergistic manner. Arch Toxicol. 2020 Apr;94(4):1303-1320. doi: 10.1007/s00204-020-02685-7. Epub 2020 Mar 2.
• [23] Tributyltin and triphenyltin induce 11-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor . Toxicol Lett. 2020 Apr 1;322:39-49. doi: 10.1016/j.toxlet.2020.01.001. Epub 2020 Jan 9.
• [24] Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses. Toxicol In Vitro. 2015 Oct;29(7):1609-18. doi: 10.1016/j.tiv.2015.06.018. Epub 2015 Jun 19.