The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer.

Abstract

<b>Purpose:</b> Activation of the PI3K pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action, and the resistance mechanisms of drugs targeting the PI3K pathway.<b>Experimental Design:</b> Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small-molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated, and RNA sequencing was performed to explore drug resistance mechanisms.<b>Results:</b> The bladder cancer cell line TCCSUP, which harbors a <i>PIK3CA</i> E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type <i>PIK3CA</i> Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with <i>PI3KCA</i> H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine <i>in vitro</i>, significantly delayed tumor growth, and prolonged survival compared with single-drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both <i>in vitro</i> and <i>in vivo</i>, and could potentially serve as a biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by cotreatment with the RAF inhibitor sorafenib. RNA sequencing of tumors resistant to treatment suggested that <i>LSP1</i> downregulation correlated with drug resistance.<b>Conclusions:</b> These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. <i>Clin Cancer Res; 23(21); 6580-91. ©2017 AACR</i>.