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
Externally publishedYes

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Neoplasms
Phosphotransferases
Ribosomal Protein S6
Phosphorylation
Ribosomal Protein S6 Kinases
S 6
Null Lymphocytes
Sirolimus
Growth
Phosphatidylinositols
Tumor Suppressor Genes
Carcinogenesis
Cell Line
temsirolimus
In Vitro Techniques

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. / Neshat, Mehran S.; Mellinghoff, Ingo K.; Tran, Chris; Stiles, Bangyan; Thomas, George; Petersen, Roseann; Frost, Philip; Gibbons, James J.; Wu, Hong; Sawyers, Charles L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 18, 28.08.2001, p. 10314-10319.

Research output: Contribution to journalArticle

Neshat, MS, Mellinghoff, IK, Tran, C, Stiles, B, Thomas, G, Petersen, R, Frost, P, Gibbons, JJ, Wu, H & Sawyers, CL 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, vol. 98, no. 18, pp. 10314-10319. https://doi.org/10.1073/pnas.171076798
Neshat, Mehran S. ; Mellinghoff, Ingo K. ; Tran, Chris ; Stiles, Bangyan ; Thomas, George ; Petersen, Roseann ; Frost, Philip ; Gibbons, James J. ; Wu, Hong ; Sawyers, Charles L. / Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 18. pp. 10314-10319.
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