Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
Ref Type | Journal Article | ||||||||||||
PMID | (28808038) | ||||||||||||
Authors | Zeng SX, Zhu Y, Ma AH, Yu W, Zhang H, Lin TY, Shi W, Tepper CG, Henderson PT, Airhart S, Guo JM, Xu CL, deVere White RW, Pan CX | ||||||||||||
Title | The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer. | ||||||||||||
|
|||||||||||||
URL | |||||||||||||
Abstract Text | 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. |
Molecular Profile | Treatment Approach |
---|
Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
---|
Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
---|
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
---|
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
---|
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
PIK3CA E545K | urinary bladder cancer | sensitive | Cisplatin + Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) and Platinol (cisplatin) synergistically inhibited Akt phosphorylation and growth of bladder cancer cells harboring PIK3CA E545K in culture (PMID: 28808038). | 28808038 |
PIK3CA E545K | urinary bladder cancer | sensitive | Pictilisib + Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) and Nexavar (sorafenib) synergistically decreased Erk and Akt phosphorylation, inhibited survival of bladder cancer cells harboring PIK3CA E545K in culture (PMID: 28808038). | 28808038 |
PIK3CA E545K | urinary bladder cancer | sensitive | Gemcitabine + Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) and Gemzar (gemcitabine) synergistically inhibited Akt phosphorylation and growth of bladder cancer cells harboring PIK3CA E545K in culture (PMID: 28808038). | 28808038 |
PTEN N48I | urinary bladder cancer | decreased response | Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) demonstrated limited inhibition of Akt phosphorylation and growth in bladder cancer cells harboring PTEN N48I in culture (PMID: 28808038). | 28808038 |
PIK3CA D549Y | urinary bladder cancer | decreased response | Pictilisib | Preclinical - Pdx | Actionable | In a preclinical study, Pictilisib (GDC-0941) demonstrated limited tumor growth inhibition and survival benefit in patient-derived xenograft (PDX) models of bladder cancer harboring PIK3CA D549Y (PMID: 28808038). | 28808038 |
PIK3CA P124L PTEN del | urinary bladder cancer | decreased response | Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) demonstrated limited inhibition of Akt phosphorylation and growth in bladder cancer cells harboring PIK3CA P124L and PTEN deletion in culture (PMID: 28808038). | 28808038 |
PIK3CA amp | urinary bladder cancer | sensitive | Gemcitabine + Pictilisib | Preclinical - Pdx | Actionable | In a preclinical study, Pictilisib (GDC-0941) and Gemzar (gemcitabine) combination treatment resulted in inhibition of Akt phosphorylation and improved tumor growth inhibition and survival compared to single agent therapy in patient-derived xenograft (PDX) models of PIK3CA amplified bladder cancer (PMID: 28808038). | 28808038 |
PIK3CA H1047R | urinary bladder cancer | sensitive | Cisplatin + Pictilisib | Preclinical - Pdx | Actionable | In a preclinical study, combination of or sequential treatment with Pictilisib (GDC-0941) and Platinol (cisplatin) significantly delayed tumor growth and prolonged survival in patient-derived xenograft (PDX) models of bladder cancer harboring PIK3CA H1047R (PMID: 28808038). | 28808038 |
PIK3CA E545K | urinary bladder cancer | sensitive | Pictilisib | Preclinical - Cell culture | Actionable | In a preclinical study, Pictilisib (GDC-0941) inhibited Akt phosphorylation, resulted in growth inhibition in bladder cancer cells harboring PIK3CA E545K in culture (PMID: 28808038). | 28808038 |
PIK3CA H1047R | urinary bladder cancer | sensitive | Pictilisib | Preclinical - Pdx | Actionable | In a preclinical study, Pictilisib (GDC-0941) inhibited Akt phosphorylation and tumor growth, prolonged survival in patient-derived xenograft (PDX) models of bladder cancer harboring PIK3CA H1047R (PMID: 28808038). | 28808038 |