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

被引:369
作者
Bianco, R
Shin, I
Ritter, CA
Yakes, FM
Basso, A
Rosen, N
Tsurutani, J
Dennis, PA
Mills, GB
Arteaga, CL
机构
[1] Vanderbilt Univ, Sch Med, Dept Med, Div Oncol, Nashville, TN 37232 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Cell Biol & Genet, New York, NY 10021 USA
[4] NCI, Ctr Canc Res, Bethesda, MD 20892 USA
[5] Univ Texas, MD Anderson Canc Ctr, Dept Mol Therapeut, Houston, TX 77030 USA
[6] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA
[7] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA
关键词
epidermal growth factor receptor; ZD1839; PTEN; tyrosine kinase inhibitors; Akt;
D O I
10.1038/sj.onc.1206388
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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)less than or equal to0.1 muM) whereas the MDA-468 cells were relatively resistant (IC50>2 muM). Low doses of ZD1839 delayed cell cycle progression and induced apoptosis in A431 cells but not in MDA-468 cells. In both cell tines, 0.1 muM ZD1839 eliminated EGFR phosphorylation. However, the basal activity of the phosphatidytinositol-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 phosphatidytinositol-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 Forkbead 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.
引用
收藏
页码:2812 / 2822
页数:11
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