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

• Published in: Clinical cancer research 2017-11, Vol.23 (21), p.6580-6591
• Main Authors: Zeng, Shu-Xiong, Zhu, Yanjun, Ma, Ai-Hong, Yu, Weimin, Zhang, Hongyong, Lin, Tzu-Yin, Shi, Wei, Tepper, Clifford G, Henderson, Paul T, Airhart, Susan, Guo, Jian-Ming, Xu, Chuan-Liang, deVere White, Ralph W, Pan, Chong-Xian
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Anticancer properties; Antitumor activity; Biomarkers; Biotechnology; Bladder; Bladder cancer; Cancer; Cell Line, Tumor; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Class I Phosphatidylinositol 3-Kinases - genetics; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Drug delivery; Drug development; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drugs; Experimental design; Extracellular signal-regulated kinase; Gemcitabine; Gene Expression Regulation, Neoplastic - drug effects; Gene sequencing; Humans; Indazoles - administration & dosage; Indazoles - adverse effects; Inhibitors; Kinases; Mathematical models; Metabolic pathways; Mice; Mutation; Phosphatidylinositol 3-Kinase - genetics; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Raf protein; Ribonucleic acid; Ribosomal protein S6; RNA; Sensitivity analysis; Signal Transduction - drug effects; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Tumor cell lines; Tumors; Urinary bladder; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelial cancer; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0033

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. 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. The bladder cancer cell line TCCSUP, which harbors a E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine , 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 and , 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 downregulation correlated with drug resistance. These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. .