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

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Neshat, Mehran S., Mellinghoff, Ingo K., Tran, Chris, Stiles, Bangyan, Thomas, George, Petersen, Roseann, Frost, Philip, Gibbons, James J., Wu, Hong, Sawyers, Charles L.·2001·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.171076798

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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.

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Authors: Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B., Thomas, G., Petersen, R., Frost, P., Gibbons, J. J., Wu, H., & Sawyers, C. L.
Venue: Proceedings of the National Academy of Sciences
Publisher: Proceedings of the National Academy of Sciences
Published: 2001-08-14
Volume: 98
Issue: 18
Pages: 10314-10319
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.171076798
OpenAlex: W2102648794
Cited by: 969
References: 6
FWCI: 21.93
Type: journal article
Language: en
Open access: green

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

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