Breast Cancer Resistance Protein Impacts Clinical Outcome in Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer

Yoh, Kiyotaka; Ishii, Genichiro; Yokose, Tomoyuki; Minegishi, Yuji; Tsuta, Kohji; Goto, Kōichi; Nishiwaki, Yutaka; Kodama, Tetsuro; Suga, Moritaka; Ochiai, Atsushi

doi:10.1158/1078-0432.ccr-0937-3

Cited by 206 publications

(180 citation statements)

References 18 publications

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“…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). Our current study further indicated that chronic treatment with gefitinib induced BCRP/ABCG2 expression through the Akt/nEGFR pathway, leading to the acquired gefitinib resistance.…”

Section: Discussionsupporting

confidence: 61%

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: Discussionsupporting

confidence: 61%

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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“…Furthermore, a previous study also showed ABCG2 to be closely associated with clinical outcome in platinum-based chemotherapy for advanced NSCLC patients. For example, ABCG2-positive patients showed a lower response effect to chemotherapy and a shorter progression-free survival and low survival rate than ABCG2-negative patients (6).…”

Section: Introductionmentioning

confidence: 97%

ABCG2 regulates the pattern of self-renewing divisions in cisplatin-resistant non-small cell lung cancer cell lines

Tang

Hou

et al. 2014

Oncology Reports

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Abstract. Overexpression of ABCG2 is considered a major mechanism of cancer drug resistance. Recent studies have shown that ABCG2 can regulate the switch between symmetric and asymmetric cell division in adult stem cells; however, the relationship between ABCG2 and cell division in drugresistant cancer cells remains to be determined. In the present study, we demonstrated that ABCG2 is involved in the cell division of drug-resistant cancer cells. We first established drug-resistant H460 and A549 cell lines by repeated exposure to cisplatin and found that the expression of ABCG2 in these cell lines was significantly increased. As evidenced by PKH-26 staining, these drug-resistant cell lines favored symmetric division, which differed from the asymmetric division of the parental cells. Furthermore, we established stable ABCG2-overexpressing and stable shRNA-ABCG2-knockdown cell lines to evaluate the potential role of ABCG2 in cancer cell division. The results showed that overexpression of ABCG2 in A549 parental cells significantly increased the proportion of symmetric division, whereas knockdown of ABCG2 in drug-resistant A549 cells significantly increased the proportion of asymmetric division. Taken together, our findings suggest that ABCG2 is involved in the modulation of cancer drug resistance by regulating the pattern of cell division. The present study provides novel insight into the role of ABCG2 in cancer treatment resistance. IntroductionChemotherapy is a key method of treatment in the primary and palliative care of patients with lung cancer, of which non-small cell lung cancer (NSCLC) accounts for the majority of cases. Cisplatin is one of the most common chemotherapeutic drugs for lung cancer treatment, particularly for NSCLC; however, many patients have resistance to cisplatin initially and secondarily (1,2). To overcome drug resistance, patients with NSCLC are administered large doses of drugs, which induce numerous adverse effects and fail to improve the clinical prognosis. Therefore, a better understanding of the molecular mechanisms underlying cisplatin resistance is warranted to further clarify the exact mechanisms underlying chemoresistance and to find or design efficient drugs to improve individual chemotherapy strategies for NSCLC patients.Increasing studies have shown that the active effluence of chemotherapeutic drugs from cancer cells is one of the main mechanisms of drug resistance. Cancer cells often exhibit drug resistance with the overexpression of membrane transport proteins, which effectively pump antitumor drugs out (3). The ATP-binding cassette (ABC) multi-drug transporters, such as ABCG2 (BCRP/MXR/ABCP), are considered to be responsible for the bulk of drug efflux in human cancer (4). Moreover, the overexpression of ABCG2 has been reported to confer drug resistance upon NSCLC to various chemotherapeutic drugs (5). Furthermore, a previous study also showed ABCG2 to be closely associated with clinical outcome in platinum-based chemotherapy for advanced NSCLC patients. For example, ABCG2-...

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“…For example, the expression of BCRP has been reported in leukemic cells (13) and solid tumors (14-16) from patients, and increased expression of BCRP has been implicated in resistance to induction therapy against childhood acute myeloid leukemia (17). Furthermore, it has been reported that levels of BCRP are higher in cases of hepatic metastasis after irinotecan-based chemotherapy than in cases of irinotecan-naive metastasis (18), and BCRP impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer (19). Therefore, inhibition of BCRP-mediated drug export could contribute to cancer chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Novel Acrylonitrile Derivatives, YHO-13177 and YHO-13351, Reverse BCRP/ABCG2-Mediated Drug ResistanceIn VitroandIn Vivo

Yamazaki

Nishiyama

Furuta

et al. 2011

Molecular Cancer Therapeutics

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Breast cancer resistance protein (BCRP/ABCG2) confers resistance to anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38, an active metabolite of irinotecan), mitoxantrone, and topotecan. In this study, we examined the reversing effects of YHO-13177, a novel acrylonitrile derivative, and its water-soluble diethylaminoacetate prodrug YHO-13351 on the BCRP-mediated drug resistance. YHO-13177 potentiated the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiated the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. In contrast, it had no effect on P-glycoprotein-mediated paclitaxel resistance in MDR1-transduced human leukemia K562 cells and multidrug resistance-related protein 1-mediated doxorubicin resistance in MRP1-transfected human epidermoid cancer KB-3-1 cells. YHO-13177 increased the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppressed the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells. In mice, YHO-13351 was rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increased the survival time of mice inoculated with BCRPtransduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone had little effect in these tumor models. These findings suggest that YHO-13351, a prodrug of YHO-13177, could be clinically useful for reversing BCRP-mediated drug resistance in cancer chemotherapy.

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Breast Cancer Resistance Protein Impacts Clinical Outcome in Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer

Cited by 206 publications

References 18 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

ABCG2 regulates the pattern of self-renewing divisions in cisplatin-resistant non-small cell lung cancer cell lines

Novel Acrylonitrile Derivatives, YHO-13177 and YHO-13351, Reverse BCRP/ABCG2-Mediated Drug ResistanceIn VitroandIn Vivo

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