The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6580-6591
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2017

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Phosphatidylinositol 3-Kinase
Urinary Bladder Neoplasms
gemcitabine
Phosphatidylinositol 3-Kinases
Heterografts
RNA Sequence Analysis
Drug Resistance
Cell Line
Cisplatin
Biomarkers
Ribosomal Protein S6
Therapeutics
Neoplasms
Mutation
MAP Kinase Signaling System
Drug Delivery Systems
Action Potentials
Research Design
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer. / Zeng, Shu Xiong; Zhu, Yanjun; Ma, Ai Hong; Yu, Weimin; Zhang, Hongyong; Lin, Tzu-Yin; Shi, Wei; Tepper, Clifford G; Henderson, Paul; Airhart, Susan; Guo, Jian Ming; Xu, Chuan Liang; deVere White, Ralph W; Pan, Chong-Xian.

In: Clinical Cancer Research, Vol. 23, No. 21, 01.11.2017, p. 6580-6591.

Research output: Contribution to journalArticle

Zeng, Shu Xiong ; Zhu, Yanjun ; Ma, Ai Hong ; Yu, Weimin ; Zhang, Hongyong ; Lin, Tzu-Yin ; Shi, Wei ; Tepper, Clifford G ; Henderson, Paul ; Airhart, Susan ; Guo, Jian Ming ; Xu, Chuan Liang ; deVere White, Ralph W ; Pan, Chong-Xian. / The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 21. pp. 6580-6591.
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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.",
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T1 - The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer

AU - Zeng, Shu Xiong

AU - Zhu, Yanjun

AU - Ma, Ai Hong

AU - Yu, Weimin

AU - Zhang, Hongyong

AU - Lin, Tzu-Yin

AU - Shi, Wei

AU - Tepper, Clifford G

AU - Henderson, Paul

AU - Airhart, Susan

AU - Guo, Jian Ming

AU - Xu, Chuan Liang

AU - deVere White, Ralph W

AU - Pan, Chong-Xian

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

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JO - Clinical Cancer Research

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