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Molecular Pharmacology

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Research ArticleArticle

Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor

Ping-Hui Tseng, Yu-Chieh Wang, Shu-Chuan Weng, Jing-Ru Weng, Chang-Shi Chen, Robert W. Brueggemeier, Charles L. Shapiro, Ching-Yu Chen, Sandra E. Dunn, Michael Pollak and Ching-Shih Chen
Molecular Pharmacology November 2006, 70 (5) 1534-1541; DOI: https://doi.org/10.1124/mol.106.023911
Ping-Hui Tseng
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Yu-Chieh Wang
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Shu-Chuan Weng
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Jing-Ru Weng
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Chang-Shi Chen
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Robert W. Brueggemeier
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Charles L. Shapiro
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Ching-Yu Chen
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Sandra E. Dunn
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Michael Pollak
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Ching-Shih Chen
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Abstract

Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27kip1, and the PDK-1 substrate p70S6K were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC50 = 3-4 μM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.

Footnotes

  • This work was supported by Public Health Service grant CA94829 and Susan G. Komen Breast Cancer Foundation grant BCTR0504187 (to C.S.C.), and translation acceleration grants from the Canadian Breast Cancer Research Initiative (to S.E.D. and M.P.).

  • ABBREVIATIONS: PI3K, phosphatidylinositol 3-kinase; PDK-1, phosphoinositide-dependent kinase-1; IGF-IR, insulin-like growth factor-I receptor; SKBR3/IGF-IR, insulin-like growth factor-I receptor-overexpressing SKBR3; CDK, cyclin-dependent kinase; COX-2, cyclooxygenase-2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; CI, combination index; PARP, poly(ADP-ribose) polymerase; OSU-03012, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide; DMEM/F12, Dulbecco's minimal essential medium/Ham's F-12; FBS, fetal bovine serum; DMSO, dimethyl sulfoxide; TBST, Tris-buffered saline/Tween 20; PBS, phosphate-buffered saline; Hsp90, 90-kDa heat shock protein; ELISA, enzyme-linked immunosorbent assay; PI, propidium iodide; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride.

    • Received February 28, 2006.
    • Accepted August 3, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor

Ping-Hui Tseng, Yu-Chieh Wang, Shu-Chuan Weng, Jing-Ru Weng, Chang-Shi Chen, Robert W. Brueggemeier, Charles L. Shapiro, Ching-Yu Chen, Sandra E. Dunn, Michael Pollak and Ching-Shih Chen
Molecular Pharmacology November 1, 2006, 70 (5) 1534-1541; DOI: https://doi.org/10.1124/mol.106.023911

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Research ArticleArticle

Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor

Ping-Hui Tseng, Yu-Chieh Wang, Shu-Chuan Weng, Jing-Ru Weng, Chang-Shi Chen, Robert W. Brueggemeier, Charles L. Shapiro, Ching-Yu Chen, Sandra E. Dunn, Michael Pollak and Ching-Shih Chen
Molecular Pharmacology November 1, 2006, 70 (5) 1534-1541; DOI: https://doi.org/10.1124/mol.106.023911
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