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

Authors

Shu-Xiong Zeng
Yanjun Zhu
Ai-Hong Ma
Weimin Yu
Hongyong Zhang
Tzu-Yin Lin
Wei Shi
Clifford G Tepper
Paul T Henderson
Susan Airhart, The Jackson LaboratoryFollow
Jian-Ming Guo
Chuan-Liang Xu
Ralph W deVere White
Chong-Xian Pan

Document Type

Article

Publication Date

11-1-2017

JAX Source

Clin Cancer Res 2017 Nov 1;23(21):6580-6591.

Volume

23

Issue

21

First Page

6580

Last Page

6591

ISSN

1078-0432

PMID

28808038

DOI

https://doi.org/10.1158/1078-0432.CCR-17-0033

Abstract

Purpose: 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.Experimental Design: 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.Results: The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type PIK3CA Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, 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 in vitro and in vivo, 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 LSP1 downregulation correlated with drug resistance.Conclusions: These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. Clin Cancer Res; 23(21); 6580-91. ©2017 AACR.

Recommended Citation

Zeng S, Zhu Y, Ma A, Yu W, Zhang H, Lin T, Shi W, Tepper C, Henderson P, Airhart S, Guo J, Xu C, deVere White R, Pan C. The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer. Clin Cancer Res 2017 Nov 1;23(21):6580-6591.