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The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor

Laboratory for Oncogenomic Research, Departments of Pediatrics (K.T., H.J., K.H., M.W., D.W.Y., A.L.S., S.E.D.), Experimental Medicine (Y.Z., C.L., S.E.D.), and Medical Genetics (J.W., S.E.D.), Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, Aachen, Germany (U.K.); Departments of Nephrology and Clinical Immunology, University Hospital Aachen, RWTH Aachen, Aachen, Germany (P.R.M.); Division of Medical Chemistry and Pharmacognosy, the Ohio State University, Columbus, Ohio (C.S.C.); Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (M.B., D.Y.)

The epidermal growth factor receptor (EGFR) is integral to basal-like and human epidermal growth factor receptor-2 (Her-2)-overexpressing breast cancers. Such tumors are associated with poor prognosis, the majority of which express high levels of EGFR. We reported that EGFR expression is induced by the oncogenic transcription factor Y-box binding protein-1 (YB-1) that occurs in a manner dependent on phosphorylation by Akt. Herein, we questioned whether blocking Akt with 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012), a phosphoinositide-dependent protein kinase-1 (PDK-1) small-molecule inhibitor, could prevent YB-1 from binding to the EGFR promoter. MDA-MB-468 and SUM 149 are basal-like breast cancer (BLBC) cells that were used for our studies because they express high levels of activated PDK-1, YB-1, and EGFR compared with the immortalized breast epithelial cell line 184htrt. In these cell lines, YB-1 preferentially bound to the –1 kilobase of the EGFR promoter, whereas this did not occur in the 184htrt cells based on chromatin immunoprecipitation. When the cells were exposed to OSU-03012 for 6 h, YB-1/EGFR promoter binding was significantly attenuated. To further confirm this observation, gel-shift assays showed that the drug inhibits YB-1/EGFR promoter binding. The inhibitory effect of OSU-03012 on EGFR was also observed at the mRNA and protein levels. OSU-03012 ultimately inhibited the growth of BLBC in monolayer and soft agar coordinate with the induction of apoptosis using an Array-Scan VTI high-content screening system. Furthermore, OSU-03012 inhibited the expression of EGFR by 48% in tumor xenografts derived from MDA-MB-435/Her-2 cells. This correlated with loss of YB-1 binding to the EGFR promoter. Hence, we find that OSU-03012 inhibits YB-1 resulting in a loss of EGFR expression in vitro and in vivo.

Address correspondence to: Dr. Sandra E. Dunn, Departments of Pediatrics, Medical Genetics and Experimental Medicine, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4 Canada. E-mail: sedunn{at}interchange.ubc.ca

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