Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics

Figures & data

Figure 1 Schematic diagram of ABCG2/BCRP protein and its amino acid variations. Amino acid variations by single-nucleotide polymorphisms are marked with stars. Transmembrane domains are shown as cylinders.

Abbreviations: ABC, adenine-triphosphate-binding cassette; BCRP, breast cancer resistance protein.

Table 1 Interactions between tyrosine kinase inhibitors and ABCG2/BCRP

Drug	Target	ABCG2/BCRP	ABCB1/P-gp	Study
Imatinib	BCR-ABL c-Kit PDGFR	+	+	Ozvegy-Laczka et al,^Citation87 Houghton et al,^Citation88 Breedveld et al,^Citation89 Burger et al,^Citation91 Thomas et al,^Citation92 Jordanides et al,^Citation93 and Liu et al^Citation94
Nilotinib	BCR-ABL c-Kit PDGFR	+	+	Brendel et al^Citation95 and Dohse et al^Citation142
Dasatinib	BCR-ABL SRC	+	+	Hiwase et al^Citation96 and Dohse et al^Citation142
Lapatinib	HER2 EGFR	+	+	Polli et al^Citation97 and Dai et al^Citation143
Ponatinib	BCR-ABL with mutations, including T315I	+	+	Sen et al^Citation115
Bosutinib	BCR-ABL mutations, except V299L and T315I SRC family	±	±	Hegedus et al^Citation116
Gefitinib	EGFR	+	+	Sugimoto et al,^Citation42 Stewart et al,^Citation98 Yanase et al,^Citation99 Carter et al,^Citation100 Elkind et al,^Citation101 Nakamura et al,^Citation102 Cusatis et al,^Citation103 Leggas et al,^Citation104 and Katayama et al^Citation105
Erlotinib	EGFR	+	+	Shi et al,^Citation107 Rudin et al,^Citation108 and Kawahara et al^Citation109
Canertinib	EGFR HER2 ERBB4	+	+	Erlichman et al^Citation106 and Minocha et al^Citation111
Sunitinib	VEGFR-1, -2, and -3 PDGFR-α/β c-Kit FLT3 RET	+	+	Shukla et al^Citation144
Pazopanib	VEGFR-1, -2, and -3 PDGFR-α/β c-Kit	+	+	Minocha et al^Citation111
Vandetanib	EGFR VEGFR-2 RET	+	+	Hegedus et al,^Citation112 Zheng et al,^Citation145 and Jovelet et al^Citation146
Axitinib	VEGFR-1,-2, and -3 PDGFR c-Kit	+	+	Poller et al^Citation114 and Reyner et al^Citation147
Sorafenib	C-RAF B-RAF VEGFR-2 PDGFR-β	+	+	Hu et al^Citation110 and Lagas et al^Citation148
Vemurafenib	B-RAF^V600E C-RAF ACK1 KHS1 SRMS	+	+	Mittapalli et al,^Citation113 Durmus et al,^Citation149 and Wu et al^Citation150
Crizotinib	ALK ROS1 c-MET	−	+	Tang et al^Citation117

Abbreviations: ABC, adenine-triphosphate-binding cassette; ABL, Abelson murine leukemia viral oncogene homolog 1; ACK1, activated CDC42 kinase 1; ALK, anaplastic lymphoma kinase; BCR, B-cell receptor; BCRP, breast cancer resistance protein; EGFR, epidermal growth factor receptor; ERBB4, erythroblastic leukemia viral oncogene homolog-4; FLT3, Fms-like tyrosine kinase 3; HER2, human epidermal growth factor receptor 2; PDGFR, platelet-derived growth factor receptor; P-gp, P-glycoprotein; VEGFR, vascular endothelial growth factor receptor; ROS1, reactive oxygen species 1.

Table 2 Single-nucleotide polymorphisms of the ABCG2/BCRP gene

Variation	Amino acid change	Location	Effect on drug action	Study
−15622C>T		Gene promoter	Increased risk of gefitinib-dependent, moderate-to-severe diarrhea. Increased pharmacokinetic parameters of erlotinib. Increased toxicity of sunitinib.	Rudin et al,^Citation108 Lemos et al,^Citation133 and van Erp et al^Citation136
−1379A>G
Δ-654/-651
−286G>C
−476T>C
Δ-235A
−113A>G
−29A>G
34G>A	V12M	N-terminal
114T>C	No change	N-terminal
151G>T	G51C	N-terminal
369C>T	No change	NBD
376C>T	Q126stop	NBD
421C>A	Q141K	NBD	Increased bioavailability of topotecan and lactone form of 9-aminocamptotecin. Increased plasma concentration of diflomotecan. Increased risk of gefitinib-induced diarrhea.	Sparreboom et al,^Citation49 Cusatis et al,^Citation103 Sparreboom et al,^Citation151 and Zamboni et al^Citation152
458C>T	T153M	NBD
474C>T	No change	NBD
496C>G	Q166E	NBD
564A>G	No change	NBD
616A>C	I206L	NBD
623T>C	F208S	NBD
742T>C	S248P	Linker
1000G>T	E334stop	Linker
1098G>A	No change	Linker
1143C>T	–	Intron	Increased risk of gefitinib-dependent, moderate-to-severe diarrhea. Increased pharmacokinetic parameters of erlotinib. Increased toxicity of sunitinib.	Rudin et al,^Citation108 Lemos et al,^Citation133 van Erp et al^Citation136
1291T>C	F431L	TMD	Insensitive to sunitinib-mediated inhibition.	Kawahara et al^Citation109
1425A>G	No change	TMD
1465T>C	F489L	TMD
1768A>T	N590Y	TMD
1858G>A	D620N	TMD
2237G>T	–
2393G>T	–
Mutations in selected cell lines R482T in MCF7 Advp3000 R482G in S1-M1-80 R482M in MT4/Dox500 R482S in 88.6/D800-B		TMD	Increased rhodamine 123 efflux, resistant to mitoxantrone/anthracyclin, and decrease of methotrexate transport.	Honjo et al,^Citation18 Allen et al,^Citation20 Volk and Schneider,^Citation153 and Wang et al^Citation154

Abbreviations: ABC, adenine-triphosphate-binding cassette; BCRP, breast cancer resistance protein; NBD, nucleotide-binding domain; TMD, transmembrane domain.

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