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‡,‖, and
- Charles L. Sawyers*,†,**
- Departments of *Medicine, ‡Medical and Molecular Pharmacology, §Pathology, †Molecular Biology Institute, and ‖Howard Hughes Medical Institute, University of California School of Medicine, Los Angeles, CA 90095; and ¶Wyeth Ayerst Research, Pearl River, NY 10965
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Edited by Richard D. Klausner, National Institutes of Health, Bethesda, MD, and approved June 26, 2001 (received for review February 15, 2001)
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.
Footnotes
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↵ ** To whom reprint requests should be addressed at: University of California Los Angeles, Hematology–Oncology, 11–934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678. E-mail: csawyers{at}mednet.ucla.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 10031.
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↵ ‡‡ Gibbons, J. J., Discafani, C., Peterson, R., Hernandez, R., Skotnicki, J. & Fruman, D. (1999) Proc. Am. Assoc. Cancer Res. 40, 301 (abstr.).
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↵ †† Raymond, E., Alexandre, J., Depenbrock, H., Mekhaldi, S., Angevin, E., Hanauske, A., Baudin, E., Escudier, B., Frisch, J., Boni, J., et al. Am. Soc. Clin. Oncol. 36th Annual Meeting, May 19–23, 2000, New Orleans, LA, 728 (abstr.).
- Abbreviations:
- FRAP/mTOR,
- mammalian target of rapamycin;
- PI3-kinase,
- phosphatidyl inositol 3-kinase;
- MEF,
- mouse embryo fibroblasts;
- ES,
- embryonic stem;
- SCID,
- severe combined immunodeficient
- Copyright © 2001, The National Academy of Sciences
