Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

TLDR

Recent evidence places the FRAP/mTOR kinase downstream of the PI3K/Akt signaling pathway, which is up‑regulated in multiple cancers due to loss of the PTEN tumor suppressor gene. The study aims to determine whether PTEN‑deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR using the rapamycin derivative CCI‑779. The authors conducted biological and biochemical experiments to assess this sensitivity. In vitro and in vivo experiments showed that PTEN‑null cells and human cancers with PTEN loss are preferentially inhibited by FRAP/mTOR blockade, that Akt‑driven tumor growth in PTEN‑positive cells is also reversed, and that increased S6 kinase activity in PTEN‑deficient cells confirms pathway activation, supporting clinical testing of FRAP/mTOR inhibitors in PTEN‑null tumors.

Abstract

Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN +/+ and PTEN −/− mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN +/+ cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.