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Molecular Cancer Therapeutics
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Companion Diagnostics and Cancer Biomarkers

Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501 In Vitro

Naoki Mine, Sayaka Yamamoto, Donald W. Kufe, Daniel D. Von Hoff and Takumi Kawabe
Naoki Mine
1CanBas Co., Ltd., Numazu, Japan.
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Sayaka Yamamoto
1CanBas Co., Ltd., Numazu, Japan.
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Donald W. Kufe
2Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Daniel D. Von Hoff
3Translational Genomics Research Institute (TGen), Phoenix, Arizona.
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Takumi Kawabe
1CanBas Co., Ltd., Numazu, Japan.
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  • For correspondence: takumi@canbas.co.jp
DOI: 10.1158/1535-7163.MCT-13-0808 Published September 2014
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Abstract

CBP501 is an anticancer drug candidate that was investigated in two randomized phase II clinical trials for patients with nonsquamous non–small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). CBP501 has been shown to have two mechanisms of action, namely calmodulin modulation and G2 checkpoint abrogation. Here, we searched for a biomarker to predict sensitivity to CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501-sensitive and -insensitive, by quantitatively analyzing the cis-diamminedichloro-platinum (II) (CDDP)–enhancing activity of CBP501 through treatments with short-term (1 hour) coexposure to CDDP and CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with CBP501 sensitivity. We found that multiple nuclear factor erythroid-2–related factor 2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines. Western blot and immunocytochemical analysis for Nrf2 in NSCLC cell lines also indicated higher protein level in CBP501-insensitive cell lines. Moreover, CBP501 sensitivity is modulated by silencing or sulforaphane-induced overexpression of Nrf2. These results indicate that Nrf2 transcription factor is a potential candidate as a biomarker for resistance to CBP501. This study might help to identify those subpopulations of patients who would respond well to the CBP501 and CDDP combination treatment of NSCLC. Mol Cancer Ther; 13(9); 2215–25. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received October 4, 2013.
  • Revision received May 1, 2014.
  • Accepted May 29, 2014.
  • ©2014 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 13 (9)
September 2014
Volume 13, Issue 9
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Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501 In Vitro
Naoki Mine, Sayaka Yamamoto, Donald W. Kufe, Daniel D. Von Hoff and Takumi Kawabe
Mol Cancer Ther September 1 2014 (13) (9) 2215-2225; DOI: 10.1158/1535-7163.MCT-13-0808

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Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501 In Vitro
Naoki Mine, Sayaka Yamamoto, Donald W. Kufe, Daniel D. Von Hoff and Takumi Kawabe
Mol Cancer Ther September 1 2014 (13) (9) 2215-2225; DOI: 10.1158/1535-7163.MCT-13-0808
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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