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Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors

Oncogene volume 22, pages 2812–2822 (2003)Cite this article

Abstract

We have examined the possible mechanisms of resistance to the epidermal growth factor receptor (EGFR) inhibitors in tumor cells with variable levels of EGFR. ZD1839 (Iressa) is a small-molecular-weight, ATP-mimetic that specifically inhibits the EGFR tyrosine kinase. A431 cell growth was markedly inhibited by ZD1839 (IC50⩽0.1 μ M) whereas the MDA-468 cells were relatively resistant (IC502 μ M). Low doses of ZD1839 delayed cell cycle progression and induced apoptosis in A431 cells but not in MDA-468 cells. In both cell lines, 0.1 μ M ZD1839 eliminated EGFR phosphorylation. However, the basal activity of the phosphatidylinositol-3 kinase (PI3 K) target Akt was eliminated in A431 but not in MDA-468 cells, implying that their Akt activity is independent of EGFR signals. A431 cells express PTEN/MMAC1/TEP, a phosphatase that can dephosphorylate position D3 of phosphatidylinositol-3,4,5 trisphosphate, the site that recruits the plecstrin-homology domain of Akt to the cell membrane. On the contrary, MDA-468 cells lack the phosphatase and tensin homolog (PTEN), potentially setting Akt activity at a high threshold that is unresponsive to EGFR inhibition alone. Therefore, we reintroduced (PTEN) by retroviral infection in MDA-468 cells. In MDA-468/PTEN but not in vector controls, treatment with ZD1839 inhibited P-Akt levels, induced relocalization of the Forkhead factor FKHRL1 to the cell nucleus, and increased FKHRL1-dependent transcriptional activity. ZD1839 induced a greater degree of apoptosis and cell cycle delay in PTEN-reconstituted than in control cells. These data suggest that loss of PTEN, by permitting a high level of Akt activity independent of receptor tyrosine kinase inputs, can temporally dissociate the inhibition of the EGFR with that of Akt induced by EGFR inhibitors. Thus, in EGFR-expressing tumor cells with concomitant amplification(s) of PI3K-Akt signaling, combined blockade of the EGFR tyrosine kinase and Akt should be considered as a therapeutic approach.

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Acknowledgements

This work was supported in part by NIH Grant R01 CA80195 (to CLA) and Vanderbilt-Ingram Comprehensive Cancer Center support Grant CA68485.

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    Roberto Bianco, Incheol Shin, Christoph A Ritter, F Michael Yakes & Carlos L Arteaga

  2. Departments of Medicine and Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Andrea Basso & Neal Rosen

  3. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Junji Tsurutani & Phillip A Dennis

  4. Department of Molecular Therapeutics, MD Anderson Cancer Center, Houston, TX, USA

    Gordon B Mills

  5. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Carlos L Arteaga

  6. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Carlos L Arteaga

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  1. Roberto Bianco
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Correspondence to Carlos L Arteaga.

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Bianco, R., Shin, I., Ritter, C. et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22, 2812–2822 (2003). https://doi.org/10.1038/sj.onc.1206388

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