Identification and Targeting of Upstream Tyrosine Kinases Mediating PI3 Kinase Activation in PTEN-Deficient Prostate Cancer
Abstract
Class IA PI3K p110 catalytic subunits are activated upon SH2 domain mediated binding of p85 regulatory subunits to tyrosine phosphorylated receptor tyrosine kinases (RTKs) or adaptor proteins. This activation can be enhanced by Ras, and is amplified by PTEN loss in the majority of advanced prostate cancers (PCa). We found that RTK inhibitors lapatinib and sorafenib could suppress PI3K in PTEN deficient PCa cells. However, analysis of p85 associated proteins by immunoblotting and LC/MS/MS failed to detect SH2 domain mediated interactions, indicating that these inhibitors were functioning downstream of PI3K. Significantly, p85 was associated primarily with p110, indicating that PTEN loss may select for increased p110beta expression due to basal RTK independent activity or activation by other mechanisms. Further studies to test this hypothesis are underway.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2009
- Accession Number
- ADA510490
Entities
People
- Steven P Balk
Organizations
- Beth Israel Deaconess Medical Center