Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas

Li, B; Chang, Chi-Ming; Yuan, Min; Shu, Hui‐Kuo G.

doi:10.1016/s0360-3016(03)01152-0

Cited by 63 publications

(75 citation statements)

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“…The inhibitory concentrations of gefitinib in NHEK were similar to those observed for blocking pEGFR and pMAPK in 22Rv1 cells (Figure 2B), an androgen-independent prostate cancer cell line (Sramkoski et al, 1999). This confirms previously reported observations of differential inhibition of EGFR and MAPK phosphorylation in glioma cell lines (Li et al, 2003) and shows the effectiveness of gefitinib against EGFR signaling in human keratinocytes. To compare the effect of gefitinib with an anti-EGFR antibody, NHEK were treated with cetuximab, an anti-EGFR humanized chimeric mouse monoclonal antibody, which competitively inhibits receptor binding of EGF and other EGFR ligands (Mendelsohn, 2001).…”

Section: Results Egfr Is the Major Her/erbb Receptor In Primary Humansupporting

confidence: 90%

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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Skin toxicity, a common drug-related adverse event observed in cancer patients treated with epidermal growth factor receptor (EGFR)-directed therapies is rarely seen with therapies targeting HER2. This study reports the significance of the EGFR and HER2 dimerization status in skin with regard to these dermatologic side effects. We demonstrate the differential effect of HER-directed therapies on the ligand driven activation status of EGFR, HER2 and MAPK in normal human epidermal keratinocytes. EGFR-directed therapies, such as gefitinib and cetuximab, inhibited ligand-induced activation of EGFR and MAPK in human keratinocytes. Pertuzumab, an antibody interfering with functional HER2 heterodimerization, failed to block ligand-induced HER signaling in primary keratinocytes. Using a novel proximity-based dimerization assay (eTagt) we show that EGFR homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies. The presence of [p]EGFR and [p]MAPK, but the absence of [p]HER2, demonstrates productive signaling via EGFR but not HER2 in human skin. These data illustrate the importance of the EGFR dimerization partner in human skin and suggests that inhibition of EGFR homodimer signaling rather than EGFR/HER2 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between EGFR-targeted versus HER2-targeted therapies.

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Section: Results Egfr Is the Major Her/erbb Receptor In Primary Humansupporting

confidence: 90%

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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“…Although a novel finding with regard to gefitinib, similar inductions of proliferation and colony formation of both EGFRand EGFRvIII-expressing cells have been described in the literature with other quinazoline tyrosine kinase inhibitors (Montgomery, 2002;Li et al, 2003). Montgomery found that the EGFR-specific quinazoline inhibitor AG1478 at a concentration of 0.1 mM stimulated colony formation of EGFRvIII-expressing cells (Montgomery, 2002).…”

Section: Discussionsupporting

confidence: 52%

“…Montgomery found that the EGFR-specific quinazoline inhibitor AG1478 at a concentration of 0.1 mM stimulated colony formation of EGFRvIII-expressing cells (Montgomery, 2002). Similarly Li et al (2003) reported that PD153035 stimulated the proliferation of LN229/EGFR cells at 0.05 mM. Thus, this seems to be a general effect of EGFR-specific quinazoline inhibitors, when used at certain concentrations.…”

Section: Discussionmentioning

confidence: 85%

Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII

Pedersen

Ottesen³

et al. 2005

Br J Cancer

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Epidermal growth factor receptor (EGFR) is frequently amplified and/or mutated in a number of human tumours and abnormal signalling from this receptor is believed to contribute to the malignant phenotype seen in these tumours. Gefitinib is a small molecule inhibitor that specifically binds and inhibits the EGFR tyrosine kinase and has been shown to inhibit the growth, proliferation, survival and invasion of a range of tumour cells overexpressing EGFR. However, clinical response to gefitinib has failed to correlate with EGFR levels and activity, indicating that other molecular mechanisms such as downstream signalling and mutations could be of importance in predicting clinical response. We therefore investigated the effect of the specific EGFR inhibitor gefitinib on the phosphorylation level, signalling and growth of cells expressing the naturally occurring constitutively active EGFR variant EGFRvIII, a low nontransforming level of EGFR and a high transforming level of EGFR. Results show that levels of gefitinib sufficient to suppress EGFR phosphorylations, EGFR-mediated proliferation and EGFR-mediated anchorage-independent growth are not sufficient to inhibit these features in cells expressing EGFRvIII. Furthermore, the data indicate that long-term exposure of EGFRvIII-expressing cells to low concentrations of gefitinib (0.01 -0.1 mM) result in increased phosphotyrosine load of the receptor, increased signalling to ERK and stimulation of proliferation and anchorage-independent growth, presumably by inducing EGFRvIII dimerisation. Higher concentrations of gefitinib (1 -2 mM), on the other hand, significantly decreased EGFRvIII phosphotyrosine load, EGFRvIII-mediated proliferation and anchorageindependent growth. Further studies are needed to investigate the implications of these important findings in the clinical setting.

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“…As potential mechanisms of ΔEGFR-independent growth, we initially suspected that ΔEGFR acquired unregulated expression or that compensatory pathways were activated that might phenocopy ΔEGFR activity (18,25). However, neither unregulated ΔEGFR overexpression nor apparent reactivation of expected downstream signaling (either as compensation for ΔEGFR or through activation of other receptor tyrosine kinases) could be observed.…”

Section: Discussionmentioning

confidence: 99%

Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence

Mukasa¹,

Wykosky²,

Ligon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and ≈50% of EGFR-amplified tumors also harbor a constitutively active mutant form of the receptor, ΔEGFR. Although ΔEGFR greatly enhances tumor growth and is thus an attractive target for anti-glioma therapies, recent clinical experiences with EGFR kinase inhibitors have been disappointing, because resistance is common and tumors eventually recur. Interestingly, it has not been established whether ΔEGFR is required for maintenance of glioma growth in vivo, and, by extension, if it truly represents a rational therapeutic target. Here, we demonstrate that in vivo silencing of regulatable ΔEGFR with doxycycline attenuates glioma growth and, therefore, that it is crucial for maintenance of enhanced tumorigenicity. Similar to the clinical experience, tumors eventually regained aggressive growth after a period of stasis, but interestingly, without re-expression of ΔEGFR. To determine how tumors acquired this ability, we found that a unique gene, KLHDC8, herein referred to as SΔE (Substitute for ΔEGFR Expression)-1, is highly expressed in these tumors, which have escaped dependence on ΔEGFR. SΔE-1 is also expressed in human gliomas and knockdown of its expression in ΔEGFR-independent "escaper" tumors suppressed tumor growth. Taken together, we conclude that ΔEGFR is required for both glioma establishment and maintenance, and that gliomas undergo selective pressure in vivo to employ alternative compensatory pathways to maintain aggressiveness in the event of EGFR silencing. Such alternative pathways function as substitutes for ΔEGFR signaling and should therefore be considered as potential targets for additional therapy.tumorigenicity | gliomblastoma | epidermal growth factor receptor

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Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas

Cited by 63 publications

References 0 publications

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII

Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence

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