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

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (P.-H.T., Y.-C.W., S.-C.W., C.-S.C., R.W.B., C.-S.C.), and Division of Hematology and Oncology, Department of Internal Medicine (C.L.S.), the Ohio State University, Columbus, Ohio; Department of Biological Science and Technology, China Medical University and Hospital, Taichung, Taiwan (J.-R.W.); Department of Family Medicine, College of Medicine, National Taiwan University, and the Gerontology Research Division, the National Health Research Institutes, Taipei, Taiwan (C.-Y.C.); British Columbia Research Institute for Children's and Women's Health, Department of Pediatrics, University of British Columbia. Vancouver, British Columbia, Canada (S.E.D.); and Department of Oncology, Jewish General Hospital, and McGill University, Montreal, Canada (M.P.)

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, p27^kip1, and the PDK-1 substrate p70^S6K 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.

Address correspondence to: Dr. Ching-Shih Chen, at College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210-1291. E-mail: chen.844{at}osu.edu

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