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Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor.
Mol Pharmacol. 2006 Nov; 70(5):1534-41.MP

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, 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 (IC(50) = 3-4 microM), 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.

Authors+Show Affiliations

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, 43210-1291, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16887935

Citation

Tseng, Ping-Hui, et al. "Overcoming Trastuzumab Resistance in HER2-overexpressing Breast Cancer Cells By Using a Novel Celecoxib-derived Phosphoinositide-dependent Kinase-1 Inhibitor." Molecular Pharmacology, vol. 70, no. 5, 2006, pp. 1534-41.
Tseng PH, Wang YC, Weng SC, et al. Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor. Mol Pharmacol. 2006;70(5):1534-41.
Tseng, P. H., Wang, Y. C., Weng, S. C., Weng, J. R., Chen, C. S., Brueggemeier, R. W., Shapiro, C. L., Chen, C. Y., Dunn, S. E., Pollak, M., & Chen, C. S. (2006). Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor. Molecular Pharmacology, 70(5), 1534-41.
Tseng PH, et al. Overcoming Trastuzumab Resistance in HER2-overexpressing Breast Cancer Cells By Using a Novel Celecoxib-derived Phosphoinositide-dependent Kinase-1 Inhibitor. Mol Pharmacol. 2006;70(5):1534-41. PubMed PMID: 16887935.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor. AU - Tseng,Ping-Hui, AU - Wang,Yu-Chieh, AU - Weng,Shu-Chuan, AU - Weng,Jing-Ru, AU - Chen,Chang-Shi, AU - Brueggemeier,Robert W, AU - Shapiro,Charles L, AU - Chen,Ching-Yu, AU - Dunn,Sandra E, AU - Pollak,Michael, AU - Chen,Ching-Shih, Y1 - 2006/08/03/ PY - 2006/8/5/pubmed PY - 2006/12/9/medline PY - 2006/8/5/entrez SP - 1534 EP - 41 JF - Molecular pharmacology JO - Mol Pharmacol VL - 70 IS - 5 N2 - 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 (IC(50) = 3-4 microM), 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16887935/Overcoming_trastuzumab_resistance_in_HER2_overexpressing_breast_cancer_cells_by_using_a_novel_celecoxib_derived_phosphoinositide_dependent_kinase_1_inhibitor_ DB - PRIME DP - Unbound Medicine ER -