Optimal induction of myeloma cell death requires dual blockade of phosphoinositide 3-kinase and mTOR signalling and is determined by translocation subtype.

ABSTRACT: Novel inhibitors of PI3K, Akt and mTOR have been developed recently, some of which have entered clinical trials. Although such compounds inhibit cell proliferation, their effects on cell survival, an important determinant of clinical response, are less distinct. Using a broad panel of myeloma cell lines and primary patient samples, we show that dual PI3K and mTOR inhibition can induce cell death. The effects are most marked in cells expressing the t(4;14) translocation, whereas t(11;14) cells are largely resistant. Using specific inhibitors of individual pathway components, we show that optimal induction of cell death requires inhibition of both PI3K and mTOR. This is due to a PI3K-independent component of mTOR activation downstream of the MAP kinase pathway. Novel mTOR kinase inhibitors,

SUBMITTER: Stengel C 

PROVIDER: S-EPMC3392205 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature