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Loss of PTEN/MMAC1/TEP in EGF Receptor-Expressing Tumor Cells Counteracts the Antitumor Action of EGFR Tyrosine Kinase Inhibitors

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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 (2003) 22, 2812–2822 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors Roberto Bianco1, Incheol Shin1, Christoph A Ritter1, F Michael Yakes1, Andrea Basso2, Neal Rosen2, Junji Tsurutani3, Phillip A Dennis3, Gordon B Mills4 and Carlos L Arteaga*,1,5,6 1Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; 2Departments of Medicine and Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 3Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; 4Department of Molecular Therapeutics, MD Anderson Cancer Center, Houston, TX, USA; 5Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; 6Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA We have examined the possible mechanisms of resistance ade of the EGFR tyrosine kinase and Akt should be to the epidermal growth factor receptor (EGFR) inhibitors considered as a therapeutic approach. in tumor cells with variable levels of EGFR. ZD1839 Oncogene (2003) 22, 2812–2822. doi:10.1038/sj.onc.1206388 (Iressa) is a small-molecular-weight, ATP-mimetic that specificallyinhibits the EGFR tyrosinekinase. A431 cell Keywords: epidermal growth factor receptor; ZD1839; growth was markedlyinhibited byZD1839 (IC 50p0.1 lm) PTEN; tyrosine kinase inhibitors; Akt whereas the MDA-468 cells were relativelyresistant (IC50>2 lm). 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 lm ZD1839 Introduction eliminated EGFR phosphorylation. However, the basal activityof the phosphatidylinositol-3 kinase (PI3 K) target The epidermal growth factor receptor (EGFR, HER1, Akt was eliminated in A431 but not in MDA-468 cells, erbB1) is a 170-kDa protein composed of an extra- implying that their Akt activity is independent of EGFR cellular ligand-binding domain, a short transmembrane signals. A431 cells express PTEN/MMAC1/TEP, a domain, and an intracellular domain with intrinsic phosphatase that can dephosphorylate position D3 of tyrosine kinase activity. Overexpression and/or hyper- phosphatidylinositol-3,4,5 trisphosphate, the site that activity of the EGFR has been shown to play a causal recruits the plecstrin-homologydomain of Akt to the cell role in the progression of several epithelial neoplasms membrane. On the contrary, MDA-468 cells lack the (reviewed in Prenzel et al., 2001; Yarden and Sliwkows- phosphatase and tensin homolog (PTEN), potentially ki, 2001). The EGFR is activated by binding of ligand(s) setting Akt activityat a high threshold that is unrespon- to its extracellular domain which leads to receptor sive to EGFR inhibition alone. Therefore, we reintroduced homodimerization or heterodimerization with any of the (PTEN) byretroviral infection in MDA-468 cells. In other three members of this family of transmembrane MDA-468/PTEN but not in vector controls, treatment tyrosine kinases: HER2 (erbB2), HER3 (erbB3), and with ZD1839 inhibited P-Akt levels, induced relocaliza- HER4 (erbB4). This results in binding of ATP to the tion of the Forkhead factor FKHRL1 to the cell nucleus, receptor’s catalytic site, activation of the receptor’s and increased FKHRL1-dependent transcriptional activ- tyrosine kinase, and autophosphorylation on C-terminal ity. ZD1839 induced a greater degree of apoptosis and cell tyrosine residues, which, in turn, recruit several cyto- cycle delay in PTEN-reconstituted than in control cells. plasmic signal transducers. These effector molecules These data suggest that loss of PTEN, bypermitting a include PLC-g1, Ras-MEK-MAPK, phosphatidylinosi- high level of Akt activityindependent of receptor tyrosine tol-3 kinase (PI3K) and its target Akt, p70S6 kinase, kinase inputs, can temporallydissociate the inhibition of Src, and STATs, among others (Olayioye et al., 2000; the EGFR with that of Akt induced byEGFR inhibitors. Yarden and Sliwkowski, 2001). Thus, in EGFR-expressing tumor cells with concomitant The oncogenic potential of the EGFR and its high amplification(s) of PI3K-Akt signaling, combined block- level of expression in tumor tissues provides a rationale for targeting this oncoprotein with novel molecular therapeutics. Indeed, anti-EGFR molecules inhibit the progression of EGFR-dependent preclinical models and *Correspondence: CL Arteaga, Division of Oncology, Vanderbilt have recently demonstrated clinical efficacy against University School of Medicine, 2220 Pierce Ave., 777 Preston Res. several human carcinomas (reviewed in Arteaga, 2001). Bldg., Nashville, TN 37232-6307, USA; E-mail: [email protected] The antitumor effect of these inhibitors requires the Received 22 August 2002; revised 10 January 2003; accepted 13 January subversion of key postreceptor signaling pathways and 2003 cell cycle/apoptosis regulatory molecules that mediate RH Loss of PTEN/MMAC1/TEP R Bianco et al 2813 the transforming effects of the EGFR network. In- kinase inhibitors alone. We have examined this hypoth- activation of constitutively active MAPK and the serine/ esis in MDA-468 human breast cancer cells which threonine kinase Akt, a target of PI3K, have been overexpress EGFR and carry a deletion and frame-shift reported in EGFR-dependent tumor cells treated with mutation at codon 70 of the PTEN protein (Lu et al., EGFR inhibitors (Fan et al., 1997; Busse et al., 2000; 1999) as well as in PTEN-expressing and PTEN-null Lenferink et al., 2000; Albanell et al., 2001; Nelson and NSCLC cell lines. Fry, 2001). In addition, inhibition of the homologous tyrosine kinase HER2 in tumor cells results in inhibition Results of PI3K and Akt (Lane et al., 2000; Hermanto et al., 2001; Lenferink et al., 2001; Moulder et al., 2001; Yakes EGFR-overexpressing cancer cells with mutant PTEN are et al., 2002). The antitumor effect of HER2 inhibitors less sensitive to ZD1839 has been shown to require the subversion of Akt function (Yakes et al., 2002). We initially examined the effects of ZD1839 (Iressa) on EGFR-mediated activation of Akt requires the A431 and MDA-468 human cancer cells. ZD1839 is an activation of PI3K. This can occur via dimerization of ATP-competitive inhibitor of the EGFR catalytic EGFR with HER3, which is able to couple to PI3K activity; it inhibits the EGFR tyrosine kinase (isolated directly (Fedi et al., 1994), or by interaction of the from A431 cell membranes) in vitro with an IC50 of receptor with the intracellular adaptor Gab1 (Rodrigues 0.033 mm (Wakeling et al., 2002). A431 and MDA-468 et al., 2000). Upon activation, PI3K converts phospha- cells exhibit EGFR gene amplification and secrete TGFa, tidylinositol-4,5 bisphosphate (PI4,5P2) to phosphati- thus expressing autoactivated EGFR in the absence of dylinositol-3,4,5 trisphosphate (PI3,4,5P3); this lipid exogenous ligands (Ennis et al., 1989; Van de Vijver recruits the plecstrin-homology (PH) domain of Akt to et al., 1991). ZD1839 inhibited the growth of (wild-type the plasma membrane where its serine/threonine kinase (WT) PTEN) A431 cells with an approximate IC50 of is activated by phosphoinositide-dependent kinase 1 0.1 mm whereas the PTEN-null MDA-468 cells were (PDK1)- and PDK2-mediated phosphorylation (Chan relatively resistant to concentrations as high as 1 mm et al., 1999). Active Akt phosphorylates a number of (Figure 1a). Similar data were obtained with the substrates involved in apoptosis, cell cycle regulation, humanized anti-EGFR IgG2 C225 (Goldstein et al., protein synthesis, and glycogen metabolism, which 1995) and the EGFR tyrosine kinase inhibitor OSI-774 include the Bcl-2 family member Bad, Forkhead (Moyer et al., 1997) (data not shown). As measured by transcription factors, caspase-9, IkB kinase, MDM2, TUNEL and flow cytometry of labeled nuclei, ZD1839 GSK-3b, p21Waf1, p27Kip1, mTOR, and nitric oxide treatment resulted in apoptosis and cell cycle delay in synthase (Datta et al., 1999; Zhou et al., 2001a, b; Shin A431 cells. These effects were not seen in MDA-468 cells et al., 2002). Via phosphorylation, Akt functionally (Figure 1b, c). To test the integrity of the PI3K pathway, inactivates these proapoptotic and cell-cycle-regulatory we used LY294002, a specific inhibitor of the p110 molecules, thus enhancing tumor cell survival and catalytic subunit of PI3K (Vlahos et al., 1994). In both proliferation. In human tumors, Akt activity has been cell lines, LY294402 induced apoptosis and cell cycle shown to be upregulated by several alterations which arrest; the latter was more marked in the PTEN-null include PI3K isoform gene amplification, activating MDA-468 than in A431 cells (Figure 1b, c). mutations of p85, Akt gene amplification and over- expression, as well as loss of function of the phosphatase ZD1839 inhibits EGFR phosphorylation and coupling to and tensin homolog (PTEN) phosphatase (Vivanco and p85 in A431 and MDA-468 cells Sawyers, 2002). PTEN dephosphorylates the D3 posi- tion of membrane PI3,4,5P3 providing negative regula- Consistent with its EGFR specificity, sub-micromolar tion of PI3K and Akt activities (Cantley and Neel, 1999; concentrations of ZD1839 induced a similar degree of Simpson and Parsons, 2001). Mutations and/or dele- inhibition of basal EGFR tyrosine phosphorylation in tions in PTEN occur with variable frequency in both A431 and MDA-468 cells without a change in advanced cancers including glioblastoma multiforme, receptor protein levels (Figure 2a). As a result of the melanoma, endometrial, breast, ovarian, renal cell, published effect of EGFR inhibitors on PI3K/Akt thyroid, and a small subset of small-cell and nonsmall- signaling and the potent ability of HER3 to couple to cell lung cancers (NSCLC) (Ali et al., 1999; Vivanco and PI3K directly (Fedi et al., 1994), we examined the effect Sawyers, 2002). Reconstitution of PTEN expression in of ZD1839 on this signaling pathway and on EGFR/ PTEN-null cells has been shown to repress Akt and HER3 interactions.
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