PI3Kβ inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways

Chenchen Feng; Yang Sun; Guanxiong Ding; Zhong Wu; Haowen Jiang; Lujia Wang; Qiang Ding; Hui Wen

doi:10.1038/srep09465

PI3Kβ inhibitor TGX221 selectively inhibits renal cell carcinoma cells with both VHL and SETD2 mutations and links multiple pathways

Sci Rep. 2015 Apr 8:5:9465. doi: 10.1038/srep09465.

Authors

Chenchen Feng¹, Yang Sun², Guanxiong Ding¹, Zhong Wu¹, Haowen Jiang¹, Lujia Wang¹, Qiang Ding¹, Hui Wen¹

Affiliations

¹ Department of Urology, Huashan Urology, Fudan University, Shanghai 200040, PR China.
² Brigham and Women's Hospital, Harvard Medical School, MA 02115, USA.

Abstract

We aimed to exploit novel compounds with high selectivity to clear cell renal cell carcinoma (ccRCC) with common mutations. Using the GDSC databases, we searched for compounds with high selectivity for ccRCC with VHL and/or SETD2 mutations. Clinical impact and gene interactions were analysed using TCGA database. In vitro and in vivo studies were performed to validate the inhibitory effects of the compound. We identified the selective PI3Kβ inhibitor TGX221 as a selective inhibitor for ccRCC with both VHL and SETD2 mutations. TGX221 also targeted cancer cells with CDKN2A and PTEN mutations. Changes in PTEN and CDKN2A gene sets were associated with worsened prognosis of ccRCC. TGX221 substantially and selectively inhibited the down stream products of VHL, SETD2, and PTEN in ccRCC cells with VHL and SETD2 mutations. TGX221 also exhibited significant selectivity in inhibiting cell motility and tumourigenesis of ccRCC cells with VHL and SETD2 mutations. TGX221 is a novel inhibitor with high selectivity for ccRCC with VHL and SETD2 mutations. It also targeted PTEN and CDKN2A mutations. How those genes were associated with PI3Kβ warranted further investigations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Carcinoma, Renal Cell / genetics*
Carcinoma, Renal Cell / metabolism
Cell Line, Tumor
Cell Movement / drug effects
Cell Movement / genetics
Cell Transformation, Neoplastic / drug effects
Cell Transformation, Neoplastic / genetics
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Drug Resistance, Neoplasm / genetics
Histone-Lysine N-Methyltransferase / genetics*
Humans
Kidney Neoplasms / genetics*
Kidney Neoplasms / metabolism
Morpholines / pharmacology*
Mutation*
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Pyrimidinones / pharmacology*
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism
Signal Transduction / drug effects
Von Hippel-Lindau Tumor Suppressor Protein / genetics*

Substances

Antineoplastic Agents
Cyclin-Dependent Kinase Inhibitor p16
Morpholines
Phosphoinositide-3 Kinase Inhibitors
Pyrimidinones
Receptor, Notch1
TGX 221
Histone-Lysine N-Methyltransferase
SETD2 protein, human
Von Hippel-Lindau Tumor Suppressor Protein
PTEN Phosphohydrolase
VHL protein, human