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

Publication ,  Journal Article
Bianco, R; Shin, I; Ritter, CA; Yakes, FM; Basso, A; Rosen, N; Tsurutani, J; Dennis, PA; Mills, GB; Arteaga, CL
Published in: Oncogene
May 8, 2003

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 (IC(50)< or =0.1 microM) whereas the MDA-468 cells were relatively resistant (IC(50)2 microM). 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 microM 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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Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

May 8, 2003

Volume

22

Issue

18

Start / End Page

2812 / 2822

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transfection
  • Recombinant Proteins
  • Phosphoric Monoester Hydrolases
  • Phosphatidylinositol 3-Kinases
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans
 

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Bianco, R., Shin, I., Ritter, C. A., Yakes, F. M., Basso, A., Rosen, N., … Arteaga, C. L. (2003). Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene, 22(18), 2812–2822. https://doi.org/10.1038/sj.onc.1206388
Bianco, Roberto, Incheol Shin, Christoph A. Ritter, F Michael Yakes, Andrea Basso, Neal Rosen, Junji Tsurutani, Phillip A. Dennis, Gordon B. Mills, and Carlos L. Arteaga. “Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors.Oncogene 22, no. 18 (May 8, 2003): 2812–22. https://doi.org/10.1038/sj.onc.1206388.
Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003 May 8;22(18):2812–22.
Bianco, Roberto, et al. “Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors.Oncogene, vol. 22, no. 18, May 2003, pp. 2812–22. Pubmed, doi:10.1038/sj.onc.1206388.
Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, Tsurutani J, Dennis PA, Mills GB, Arteaga CL. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003 May 8;22(18):2812–2822.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

May 8, 2003

Volume

22

Issue

18

Start / End Page

2812 / 2822

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transfection
  • Recombinant Proteins
  • Phosphoric Monoester Hydrolases
  • Phosphatidylinositol 3-Kinases
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Lung Neoplasms
  • Humans