Identification and Targeting of Upstream Tyrosine Kinases Mediating PI3 Kinase Activation in PTEN-Deficient Prostate Cancer
Annual rept. 1 Jun 2008-31 May 2009
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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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 LCMSMS 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.
- Medicine and Medical Research