Data from Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014.</p><p><b>Experimental Design:</b> The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-resistant CRPC cell lines <i>in vitro</i> and in murine models. Both soft tissue and bone sites were evaluated <i>in vivo</i>. Impacts on cell proliferation, apoptosis, cancer stem cells, and angiogenesis were evaluated.</p><p><b>Results:</b> The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014–induced inhibition of Notch pathway signaling; decreased survival signals (cyclin E; MEK/ERK, PI3K/AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved caspase-3); reduced microvessel density; reduced epithelial–mesenchymal transition; and reduced cancer stem–like cells in the tumor.</p><p><b>Conclusions:</b> These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC. <i>Clin Cancer Res; 21(20); 4619–29. ©2015 AACR</i>.</p><p><i>See related commentary by Zhang and Armstrong, p. 4505</i></p></div>