Breast cancer resistance protein: Molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics

Sugimoto, Yoshikazu; Tsukahara, Satomi; Ishikawa, Etsuko; Mitsuhashi, Junko

doi:10.1111/j.1349-7006.2005.00081.x

Cited by 84 publications

(75 citation statements)

References 38 publications

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“…Several studies have demonstrated that gefitinib is also a substrate of BCRP/ABCG2 at low concentrations (44 -46). Stable transfection of A431 with BCRP/ABCG2 cDNA resulted in insensitivity of cells to gefitinib (47). BCRP/ABCG2 expression by immunohistochemical staining was detected in 46% of treatment-naive NSCLC patients (59).…”

Section: Discussionmentioning

confidence: 97%

“…In fact, several studies have shown that gefitinib is also a BCRP/ABCG2 substrate (44 -46), and stably enforced BCRP/ABCG2 expression in A431 cells conferred gefitinib resistance (47). Furthermore, as mentioned above, a case report showed that a wtEGFR-expressing NSCLC patient developed acquired gefitinib resistance without any identifiable EGFR mutations.…”

Section: Phosphorylation Of Egfr At Ser-229 By Akt Is Critical For Egmentioning

confidence: 95%

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Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

Huang

Chen

et al. 2011

Journal of Biological Chemistry

163

140

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Epidermal growth factor receptor (EGFR), an aberrantly overexpressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for nonsmall cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ ABCG2 expression.

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Section: Discussionmentioning

confidence: 97%

Section: Phosphorylation Of Egfr At Ser-229 By Akt Is Critical For Egmentioning

confidence: 95%

Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

Huang

Chen

et al. 2011

Journal of Biological Chemistry

163

140

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“…(32) Moreover, genetic polymorphisms of the ABC transporters are associated with modulations in functional transporter activity. (4,33) Therefore, it is difficult to predict the possible pharmacological interactions between TKIs, anticancer drugs, and ABC transporters in individual patient based on the current insufficient evidence.…”

mentioning

confidence: 99%

“…(1,3) BCRP is referred to as a half-type ABC transporter that functions as a homodimer and transports anticancer agents such as topotecan, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), methotrexate, and MXR out of cells. (4) Many compounds have been tested for their ability to overcome ABC transporter-mediated drug resistance. Verapamil, cyclosporine A (CsA), and other compounds have been identified as inhibitors of P-gp, (5,6) while fumitremorgin C (FTC), tamoxifen derivatives, and certain flavonoids inhibit BCRP.…”

mentioning

confidence: 99%

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

et al. 2010

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Sunitinib malate (Sutent, SU11248) is a small-molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP-binding cassette transporter, P-glycoprotein (P-gp) ⁄ ABCB1, multidrug resistance-associated protein 1 (MRP1) ⁄ ABCC1, and breast cancer resistance protein (BCRP) ⁄ ABCG2. Here, we analyzed the effects of sunitinib on P-gp and on wild-type and germ-line mutant BCRPs. Sunitinib remarkably reversed BCRP-mediated and partially reversed P-gp-mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate transport and P-gp-mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K-, R482G-, R482S-, and F431L-variant BCRPs. Intriguingly, the F431L-variant BCRP, which is expressed by a germ-line mutant allele 1291T>C, was almost insensitive to both sunitinib-and fumitremorgin C (FTC)-mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit 125 I-iodoarylazidoprazosin-binding to F431L-BCRP. Thus, residue Phe-431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ-line variation of the BCRP ⁄ ABCG2 gene on the pharmacological interaction between small-molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy. (Cancer Sci 2010; 101: 1493-1500 T he ATP-binding cassette (ABC) transporter proteins, particularly P-glycoprotein (P-gp ⁄ ABCB1), multidrug resistance-associated protein 1 (MRP1 ⁄ ABCC1), and breast cancer resistance protein (BCRP ⁄ MXR ⁄ ABCP ⁄ ABCG2) have been extensively studied as key molecules that are involved in the multidrug-resistant phenotype of cancer cells.(1,2) P-gp effluxes various anticancer agents including vincristine (VCR), paclitaxel (PTX), doxorubicin (DOX), and mitoxantrone (MXR). (1,3) BCRP is referred to as a half-type ABC transporter that functions as a homodimer and transports anticancer agents such as topotecan, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), methotrexate, and MXR out of cells. Many compounds have been tested for their ability to overcome ABC transporter-mediated drug resistance. Verapamil, cyclosporine A (CsA), and other compounds have been identified as inhibitors of P-gp, (5,6) while fumitremorgin C (FTC), tamoxifen derivatives, and certain flavonoids inhibit BCRP.(7-10) Verapamil, for example, directly interacts with P-gp and competitively interferes with transporter-substrate binding. (11) Co-administration of inhibitory compounds would be expected to overcome unwanted anticancer drug resistance during chemotherapy, but is also suspected to affect the pharmacokinetics and pharmacodynamics of substrate anticancer drugs....

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“…The breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that forms a functional homodimer and pumps various drugs out of the cell, conferring resistance to a variety of anticancer agents. Sugimoto et al 68 reported that overexpression of BCRP confers resistance to gefitinib, topotecan, 7-ethyl-10-hydroxycamptothecin, and mitoxantrone. They reported that BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) and BCRP-transduced human non-small cell lung cancer PC-9 (PC-9/BCRP) cells have acquired cellular resistance to gefitinib.…”

Section: Acquired Resistance To Tkismentioning

confidence: 99%

Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

Liu²,

Chen³

et al. 2010

Cancer Biology & Therapy

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Breast cancer resistance protein: Molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics

Cited by 84 publications

References 38 publications

Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

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