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

Mehran S. Neshat, Ingo K. Mellinghoff, Chris Tran, Bangyan Stiles, George Thomas, Roseann Petersen, Philip Frost, James J. Gibbons, Hong Wu, Charles L. Sawyers

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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.

Original languageEnglish (US)
Pages (from-to)10314-10319
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number18
DOIs
StatePublished - Aug 28 2001

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    Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B., Thomas, G., Petersen, R., Frost, P., Gibbons, J. J., Wu, H., & Sawyers, C. L. (2001). Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proceedings of the National Academy of Sciences of the United States of America, 98(18), 10314-10319. https://doi.org/10.1073/pnas.171076798