Feedback suppression of PI3K? signaling in PTEN-mutated tumors is relieved by selective inhibition of PI3K?.

ABSTRACT: In PTEN-mutated tumors, we show that PI3K? activity is suppressed and PI3K signaling is driven by PI3K?. A selective inhibitor of PI3K? inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3K? only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3K? and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3K? and PI3K?. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.

SUBMITTER: Schwartz S 

PROVIDER: S-EPMC4293347 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature