Details of the Drug Combination

General Information of Drug Combination (ID: DC2J8AA)

• Drug Combination Name: Gefitinib + Pemetrexed
• Indication: Lung Neoplasms; Status: Phase 3 [1]
• Component Drugs:
  Gefitinib (DM15F0X): Small molecular drug
  Pemetrexed (DMMX2E6): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Gefitinib

Disease Entry	ICD 11	Status	REF
Colon adenocarcinoma	N.A.	Approved	[2]
Glioblastoma	2A00	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Rectal adenocarcinoma	2B92	Approved	[2]
Rectum mucinous adenocarcinoma	N.A.	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Approved	[3]
Head and neck cancer	2D42	Phase 3	[3]
Urethral cancer	2C93	Phase 2	[3]
Colon cancer	2B90.Z	Investigative	[2]
Colon mucinous adenocarcinoma	N.A.	Investigative	[2]

Gefitinib 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	[11]

Gefitinib Interacts with 4 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	[13]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[14]

Gefitinib Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]

Gefitinib Interacts with 103 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases ADR	[17]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Response To Substance	[18]
Sulfhydryl oxidase 1 (QSOX1)	OT4ZPK4P	QSOX1_HUMAN	Increases Expression	[19]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Decreases Expression	[19]
Interferon alpha-inducible protein 6 (IFI6)	OTWOOAM4	IFI6_HUMAN	Decreases Expression	[19]
Fibroblast growth factor 6 (FGF6)	OTRJ679P	FGF6_HUMAN	Increases Expression	[19]
Ski oncogene (SKI)	OT4KJ8F6	SKI_HUMAN	Increases Expression	[19]
Erythropoietin receptor (EPOR)	OTUIOEU3	EPOR_HUMAN	Increases Expression	[19]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[19]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)	OTDS2EAR	TNR1B_HUMAN	Decreases Expression	[19]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[19]
Cytochrome P450 2F1 (CYP2F1)	OTY3HJH1	CP2F1_HUMAN	Decreases Expression	[19]
Replication protein A 70 kDa DNA-binding subunit (RPA1)	OT76POLP	RFA1_HUMAN	Increases Expression	[19]
Adenosine receptor A1 (ADORA1)	OTI7X39E	AA1R_HUMAN	Decreases Expression	[19]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[19]
DNA mismatch repair protein Mlh1 (MLH1)	OTG5XDD8	MLH1_HUMAN	Decreases Expression	[19]
Glycine--tRNA ligase (GARS1)	OT5B6R9Y	GARS_HUMAN	Increases Expression	[19]
Epidermal growth factor receptor substrate 15 (EPS15)	OT7NPP8U	EPS15_HUMAN	Increases Expression	[19]
Neuronal pentraxin-2 (NPTX2)	OT3SSJDP	NPTX2_HUMAN	Decreases Expression	[19]
Leptin receptor (LEPR)	OT9H7G0C	LEPR_HUMAN	Decreases Expression	[19]
Neural retina-specific leucine zipper protein (NRL)	OT65MFKQ	NRL_HUMAN	Decreases Expression	[19]
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 (GNB2)	OT3JPRCQ	GBB2_HUMAN	Decreases Expression	[19]
Retinal guanylyl cyclase 1 (GUCY2D)	OT81UJI0	GUC2D_HUMAN	Decreases Expression	[19]
Cell growth regulator with RING finger domain protein 1 (CGRRF1)	OTLMNRCL	CGRF1_HUMAN	Increases Expression	[19]
Dual specificity protein phosphatase 9 (DUSP9)	OTZZWEQL	DUS9_HUMAN	Decreases Expression	[19]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[20]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[21]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[21]
Telomerase reverse transcriptase (TERT)	OT085VVA	TERT_HUMAN	Decreases Expression	[22]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[23]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[24]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[25]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[7]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[26]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[27]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Phosphorylation	[28]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Phosphorylation	[29]
HLA class II histocompatibility antigen, DO alpha chain (HLA-DOA)	OTZE5Q7R	DOA_HUMAN	Affects Expression	[27]
Heat shock protein HSP 90-alpha (HSP90AA1)	OTLG1WPK	HS90A_HUMAN	Increases Secretion	[26]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Increases Phosphorylation	[30]
High mobility group protein B1 (HMGB1)	OT4B7CPF	HMGB1_HUMAN	Increases Secretion	[26]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[31]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Secretion	[26]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[32]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[7]
Platelet endothelial cell adhesion molecule (PECAM1)	OTXOM4D9	PECA1_HUMAN	Decreases Expression	[7]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[24]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[33]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[18]
DnaJ homolog subfamily B member 1 (DNAJB1)	OTCOSEVH	DNJB1_HUMAN	Increases Secretion	[26]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Expression	[34]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Expression	[34]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Increases Activity	[26]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[18]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Affects Expression	[27]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[35]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[23]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[24]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B)	OTAG24N1	CDN2B_HUMAN	Increases Expression	[25]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Decreases Phosphorylation	[7]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[18]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Response To Substance	[36]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[31]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[22]
Caveolin-1 (CAV1)	OTEZUR1L	CAV1_HUMAN	Increases Expression	[34]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[37]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[38]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[36]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[39]
MHC class I polypeptide-related sequence B (MICB)	OTS2DVDW	MICB_HUMAN	Increases Expression	[40]
MHC class I polypeptide-related sequence A (MICA)	OTPEIEAR	MICA_HUMAN	Increases Expression	[40]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Increases Expression	[41]
Serine protease HTRA1 (HTRA1)	OTR8ACBF	HTRA1_HUMAN	Increases Expression	[42]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[27]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[24]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[43]
MARVEL domain-containing protein 1 (MARVELD1)	OT5CPOJE	MALD1_HUMAN	Decreases Response To Substance	[44]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Decreases Response To Substance	[45]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Affects Response To Substance	[46]
Membrane-associated progesterone receptor component 1 (PGRMC1)	OTBE6WAC	PGRC1_HUMAN	Decreases Response To Substance	[47]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Response To Substance	[48]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Affects Response To Substance	[49]
RNA-binding protein 7 (RBM7)	OTFIWTMF	RBM7_HUMAN	Affects Response To Substance	[49]
Cell death regulator Aven (AVEN)	OTGIN5YK	AVEN_HUMAN	Affects Response To Substance	[49]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Response To Substance	[50]
Phospholipase B-like 1 (PLBD1)	OTHYEB4W	PLBL1_HUMAN	Affects Response To Substance	[49]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[51]
Securin (PTTG1)	OTIMYS4W	PTTG1_HUMAN	Decreases Response To Substance	[31]
Amphiregulin (AREG)	OTJFOR67	AREG_HUMAN	Decreases Response To Substance	[49]
Pleckstrin homology-like domain family A member 2 (PHLDA2)	OTMV9DPP	PHLA2_HUMAN	Affects Response To Substance	[49]
Aurora kinase A (AURKA)	OTMX0HYT	AURKA_HUMAN	Decreases Response To Substance	[51]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Affects Response To Substance	[10]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Response To Substance	[52]
Ceramide transfer protein (CERT1)	OTNUCNHX	CERT_HUMAN	Affects Response To Substance	[49]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Affects Response To Substance	[53]
Oncostatin-M-specific receptor subunit beta (OSMR)	OTORWHPL	OSMR_HUMAN	Affects Response To Substance	[49]
Protransforming growth factor alpha (TGFA)	OTPD1LL9	TGFA_HUMAN	Decreases Response To Substance	[54]
Dual specificity protein phosphatase 3 (DUSP3)	OTPJX9B4	DUS3_HUMAN	Affects Response To Substance	[49]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Response To Substance	[51]
Pericentrin (PCNT)	OTW4Z65J	PCNT_HUMAN	Decreases Response To Substance	[47]
Coronin-1C (CORO1C)	OTXDF9T3	COR1C_HUMAN	Affects Response To Substance	[49]
Ribonucleoside-diphosphate reductase large subunit (RRM1)	OTXGQOR9	RIR1_HUMAN	Affects Response To Substance	[10]

Indication(s) of Pemetrexed

Disease Entry	ICD 11	Status	REF
Central nervous system lymphoma	2B33.5	Approved	[4]
Epithelioid mesothelioma	2F10	Approved	[4]
Lung cancer	2C25.0	Approved	[4]
Malignant pleural mesothelioma	2C26.0	Approved	[5]
Non-small-cell lung cancer	2C25.Y	Approved	[4]
Sarcomatoid mesothelioma	N.A.	Approved	[4]
Small-cell lung cancer	2C25.Y	Approved	[4]
Lung neoplasm	N.A.	Investigative	[4]

Pemetrexed Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[57]

Pemetrexed Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[58]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[59]
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[60]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[61]
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[62]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[63]

Pemetrexed Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proton-coupled folate transporter (SLC46A1)	OT049V7Y	PCFT_HUMAN	Increases Activity	[64]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Increases Response To Substance	[65]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Decreases Response To Substance	[66]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[67]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Decreases Expression	[68]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[69]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[70]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Increases Response To Substance	[71]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Increases Response To Substance	[71]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Decreases Response To Substance	[72]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Response To Substance	[55]
Gamma-glutamyl hydrolase (GGH)	OTL71J7T	GGH_HUMAN	Affects Response To Substance	[56]
Nucleophosmin (NPM1)	OTTBYYT0	NPM_HUMAN	Decreases Response To Substance	[73]
ALK tyrosine kinase receptor (ALK)	OTV3P4V8	ALK_HUMAN	Affects Response To Substance	[74]
ATP-binding cassette sub-family C member 11 (ABCC11)	OTVHL7OR	MRP8_HUMAN	Decreases Response To Substance	[75]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Increases Response To Substance	[71]
Folylpolyglutamate synthase, mitochondrial (FPGS)	OTW3F1ZE	FOLC_HUMAN	Increases Response To Substance	[56]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Response To Substance	[67]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Carcinoma, Non Small Cell Lung	DC32TE0	N. A.	Phase 1	[76]

References

• [1] ClinicalTrials.gov (NCT02518802) Pemetrexed Combined With Synchronous Gefitinib as Adjuvent Therapy in Patient With EGFR Mutant Lung Adenocarcinoma
• [2] Gefitinib 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: 4941).
• [4] Pemetrexed 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: 6837).
• [6] Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase. Mol Cancer Ther. 2008 Mar;7(3):599-606.
• [7] Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways. World J Gastrointest Oncol. 2022 Feb 15;14(2):450-477. doi: 10.4251/wjgo.v14.i2.450.
• [8] EGFR inhibitors enhanced the susceptibility to NK cell-mediated lysis of lung cancer cells. J Immunother. 2011 May;34(4):372-81. doi: 10.1097/CJI.0b013e31821b724a.
• [9] Overcoming acquired resistance of gefitinib in lung cancer cells without T790M by AZD9291 or Twist1 knockdown in vitro and in vivo. Arch Toxicol. 2019 Jun;93(6):1555-1571. doi: 10.1007/s00204-019-02453-2. Epub 2019 Apr 16.
• [10] DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma. Cancer. 2011 Jul 15;117(14):3201-8. doi: 10.1002/cncr.25863. Epub 2011 Jan 24.
• [11] Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer. 2004 Feb 9;90(3):566-72.
• [12] Gefitinib-phenytoin interaction is not correlated with the C-erythromycin breath test in healthy male volunteers. Br J Clin Pharmacol. 2009 Aug;68(2):226-37.
• [13] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [14] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [15] Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7.
• [16] Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet. 2005;44(10):1067-81.
• [17] Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst. 2006 Dec 6;98(23):1739-42.
• [18] Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 2006 Jun 1;66(11):5542-8. doi: 10.1158/0008-5472.CAN-05-4620.
• [19] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [20] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [21] Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells. Environ Toxicol. 2018 Nov;33(11):1153-1159.
• [22] Antiproliferative effects of gefitinib are associated with suppression of E2F-1 expression and telomerase activity. Anticancer Res. 2006 Sep-Oct;26(5A):3387-91.
• [23] Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells. Toxicol Appl Pharmacol. 2017 Nov 15;335:16-27. doi: 10.1016/j.taap.2017.09.017. Epub 2017 Sep 21.
• [24] EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One. 2011;6(6):e18691. doi: 10.1371/journal.pone.0018691. Epub 2011 Jun 2.
• [25] ZD1839 induces p15INK4b and causes G1 arrest by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Mol Cancer Ther. 2007 May;6(5):1579-87. doi: 10.1158/1535-7163.MCT-06-0814.
• [26] Reactive metabolite of gefitinib activates inflammasomes: implications for gefitinib-induced idiosyncratic reaction. J Toxicol Sci. 2020;45(11):673-680. doi: 10.2131/jts.45.673.
• [27] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [28] Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat. 2006 Mar;96(2):131-46. doi: 10.1007/s10549-005-9070-2. Epub 2005 Oct 27.
• [29] Epidermal growth factor receptor activity determines response of colorectal cancer cells to gefitinib alone and in combination with chemotherapy. Clin Cancer Res. 2005 Oct 15;11(20):7480-9. doi: 10.1158/1078-0432.CCR-05-0328.
• [30] Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007 May 1;13(9):2795-803. doi: 10.1158/1078-0432.CCR-06-2077.
• [31] Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells. Chem Biol Interact. 2013 Apr 25;203(2):412-22. doi: 10.1016/j.cbi.2013.03.011. Epub 2013 Mar 22.
• [32] Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib. Toxicol Lett. 2021 Mar 1;338:1-9. doi: 10.1016/j.toxlet.2020.11.011. Epub 2020 Nov 25.
• [33] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [34] Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance. Breast Cancer Res Treat. 2010 Feb;119(3):575-91. doi: 10.1007/s10549-009-0355-8. Epub 2009 Mar 15.
• [35] Dihydromyricetin suppresses tumor growth via downregulation of the EGFR/Akt/survivin signaling pathway. J Biochem Mol Toxicol. 2023 Jun;37(6):e23328. doi: 10.1002/jbt.23328. Epub 2023 Feb 19.
• [36] The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells. J Toxicol Sci. 2019;44(6):435-440. doi: 10.2131/jts.44.435.
• [37] Autophagy Inhibition Overcomes the Antagonistic Effect Between Gefitinib and Cisplatin in Epidermal Growth Factor Receptor Mutant Non--Small-Cell Lung Cancer Cells. Clin Lung Cancer. 2015 Sep;16(5):e55-66. doi: 10.1016/j.cllc.2015.03.006. Epub 2015 Apr 2.
• [38] Nrf2 but not autophagy inhibition is associated with the survival of wild-type epidermal growth factor receptor non-small cell lung cancer cells. Toxicol Appl Pharmacol. 2016 Nov 1;310:140-149. doi: 10.1016/j.taap.2016.09.010. Epub 2016 Sep 14.
• [39] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [40] Susceptibility to natural killer cell-mediated lysis of colon cancer cells is enhanced by treatment with epidermal growth factor receptor inhibitors through UL16-binding protein-1 induction. Cancer Sci. 2012 Jan;103(1):7-16. doi: 10.1111/j.1349-7006.2011.02109.x. Epub 2011 Nov 15.
• [41] Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects. Biomed Pharmacother. 2010 Feb;64(2):88-92. doi: 10.1016/j.biopha.2009.06.010. Epub 2009 Oct 23.
• [42] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [43] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [44] Inhibition of SREBP increases gefitinib sensitivity in non-small cell lung cancer cells. Oncotarget. 2016 Aug 9;7(32):52392-52403.
• [45] The K-Ras effector p38 MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation. J Biol Chem. 2017 Sep 8;292(36):15070-15079. doi: 10.1074/jbc.M117.779488. Epub 2017 Jul 24.
• [46] Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am J Respir Crit Care Med. 2011 Apr 15;183(8):1071-9. doi: 10.1164/rccm.201009-1440OC. Epub 2010 Oct 29.
• [47] Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance. Toxicol Appl Pharmacol. 2015 Nov 1;288(3):359-73. doi: 10.1016/j.taap.2015.08.008. Epub 2015 Aug 20.
• [48] Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells. Toxicol In Vitro. 2017 Oct;44:36-43.
• [49] Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). Hum Mol Genet. 2004 Dec 15;13(24):3029-43. doi: 10.1093/hmg/ddh331. Epub 2004 Oct 20.
• [50] The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3169-79. doi: 10.1158/1535-7163.MCT-07-0507.
• [51] Aurora-A promotes gefitinib resistance via a NF-B signaling pathway in p53 knockdown lung cancer cells. Biochem Biophys Res Commun. 2011 Feb 11;405(2):168-72. doi: 10.1016/j.bbrc.2011.01.001. Epub 2011 Jan 7.
• [52] BIM induction of apoptosis triggered by EGFR-sensitive and resistance cell lines of non-small-cell lung cancer. Med Oncol. 2011 Jun;28(2):572-7. doi: 10.1007/s12032-010-9470-y. Epub 2010 Mar 17.
• [53] E3 ubiquitin ligase RNF180 reduces sensitivity of triple-negative breast cancer cells to Gefitinib by downregulating RAD51. Chem Biol Interact. 2022 Feb 25;354:109798. doi: 10.1016/j.cbi.2022.109798. Epub 2022 Jan 6.
• [54] Increases of amphiregulin and transforming growth factor-alpha in serum as predictors of poor response to gefitinib among patients with advanced non-small cell lung cancers. Cancer Res. 2005 Oct 15;65(20):9176-84. doi: 10.1158/0008-5472.CAN-05-1556.
• [55] Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer. 2007 Mar 12;96(5):769-75.
• [56] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.
• [57] Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40.
• [58] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [59] pH-Dependent transport of pemetrexed by breast cancer resistance protein. Drug Metab Dispos. 2011 Sep;39(9):1478-85.
• [60] Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci. 2006 Apr;27(5):524-32.
• [61] Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol. 2012 Feb;81(2):134-42.
• [62] Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr. 2014;73:175-204.
• [63] The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol. 2008 Sep;74(3):854-62.
• [64] Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits -glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64.
• [65] The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Mol Cancer Ther. 2006 Feb;5(2):438-49. doi: 10.1158/1535-7163.MCT-05-0243.
• [66] The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
• [67] Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 2011 Nov;47(16):2471-8. doi: 10.1016/j.ejca.2011.06.003. Epub 2011 Jul 2.
• [68] Pemetrexed downregulates ERCC1 expression and enhances cytotoxicity effected by resveratrol in human nonsmall cell lung cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2013 Dec;386(12):1047-59. doi: 10.1007/s00210-013-0905-9. Epub 2013 Aug 3.
• [69] The roles of thymidylate synthase and p53 in regulating Fas-mediated apoptosis in response to antimetabolites. Clin Cancer Res. 2004 May 15;10(10):3562-71. doi: 10.1158/1078-0432.CCR-03-0532.
• [70] Xanthohumol inhibits non-small cell lung cancer by activating PUMA-mediated apoptosis. Toxicology. 2022 Mar 30;470:153141. doi: 10.1016/j.tox.2022.153141. Epub 2022 Mar 5.
• [71] KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
• [72] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.
• [73] Proteomic identification of differentially expressed proteins associated with the multiple drug resistance in methotrexate-resistant human breast cancer cells. Int J Oncol. 2014 Jul;45(1):448-58.
• [74] Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol. 2011 Apr;6(4):774-80. doi: 10.1097/JTO.0b013e31820cf053.
• [75] ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci. 2010 Nov;101(11):2404-10.
• [76] ClinicalTrials.gov (NCT01469000) A Study of Pemetrexed and Gefitinib Versus Gefitinib in Non-Small Cell Lung Cancer (NSCLC)