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| Status |
Public on Oct 24, 2017 |
| Title |
The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Activation of the phosphatidylinositol 3-kinase (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 resistant 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 PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than a model with wild-type. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug targeted 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 biomarker to predict response to pictilisib. The inhibitor activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation might play a role in inducing drug resistance. These preclinical results provide new insight into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.
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| Overall design |
A total of 9 samples were analyzed by transcriptome sequencing (RNA-seq) in this study. The study included BL0269 bladder cancer patient-derived xenograft (PDX) tumors derived from subcutaneous injection of tumor pieces into 10 mice. Mice were randomized into 5 treatment groups: control (untreated), cisplatin, pictilisib (GDC-0941), combination (cisplatin+pictilisib), and sequential (cisplatin -> pictilisib) treatments. Each treatment group had biological duplicate tumors from two separate mice.
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| Contributor(s) |
Pan C, Tepper CG |
| Citation(s) |
28808038 |
| Submission date |
Jul 13, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Clifford G. Tepper |
| E-mail(s) |
cgtepper@ucdavis.edu
|
| Phone |
916-734-7195
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| Organization name |
UC Davis School of Medicine
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| Department |
Biochemistry and Molecular Medicine
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| Street address |
4645 2nd Avenue, Room 2300A
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| City |
Sacramento |
| State/province |
CA |
| ZIP/Postal code |
95817 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA394145 |
| SRA |
SRP111868 |
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