Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non–small cell lung cancer cells

Schaeybroeck, Sandra Van; Kyula, Joan; Kelly, Donal M.; Karaı̈skou, Anthi; Stokesberry, Susan; Cutsem, Éric Van; Longley, Daniel B.; Johnston, Patrick G.

doi:10.1158/1535-7163.mct-05-0446

Cited by 86 publications

(73 citation statements)

References 49 publications

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“…The H1975 cell line carrying the L858R and T790M mutations was resistant to gefitinib [7]; the H1650 cell line, despite harboring a delE746_A750 activating mutation in the exon 19 of the EGFR gene, was resistant to gefitinib and erlotinib as previously reported [28][29][30]; K-RAS mutations were found in four of the tested resistant cell lines.…”

Section: Resultssupporting

confidence: 71%

“…The response of sensitive cell lines to gefitinib was previously correlated with dependence on AKT and MAPK activation in response to EGFR signaling [34] and on inhibition of both PI3K/AKT/mTOR and MAPK pathways following gefitinib treatment [28,35,36]. In the three highly sensitive cell lines we observed a marked reduction on p-p44/42 MAPK, on p-AKT, and on p-S6K following gefitinib treatment (Fig.…”

Section: Discussionsupporting

confidence: 62%

“…The gefitinib concentration of 1 M was used as cutoff for sensitivity because this concentration approaches levels observed in serum from patients under treatment with 250 mg/day [6]. In line with other reports [28,33,34] no association between responsiveness to gefitinib and EGFR level was observed.…”

Section: Discussionmentioning

confidence: 59%

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Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

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Section: Resultssupporting

confidence: 71%

Section: Discussionsupporting

confidence: 62%

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Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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“…A significant antagonism was observed between gefitinib-and oxaliplatin-induced cell death in cell lines with low basal EGFR phosphorylation levels, whereas in cell lines with high basal EGFR phosphorylation, the interaction between gefitinib and oxaliplatin was additive and often supraadditive/synergistic (Van Schaeybroeck et al, 2005). Similar results were obtained in human NSCLC cells (Van Schaeybroeck et al, 2006). However, different data were obtained for cetuximab preclinical antitumour activity (monotherapy and combination based), which was not predicted by relative total or activated EGFR tumour expression levels (Wild et al, 2006).…”

Section: A Ray Of Hopesupporting

confidence: 75%

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

Milano

Leyland‐Jones

2008

Br J Cancer

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The clinical experience recently reported with epidermal growth factor receptor (EGFR)-targeting drugs confirms the synergistic interactions observed between these compounds and conventional cytotoxic agents, which were previously established at the preclinical stage. There are, however, examples of major gaps between the bench and the bedside. Particularly demonstrative is the failure of the tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) combined with chemotherapy in pretreated nonsmall cell lung cancer patients. These discrepancies can be due to several factors such as the methodology used to evaluate TKI plus cytotoxic agent combinations in preclinical models and the insufficient consideration given to the importance of the drug sequences for the tested combinations. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve their clinical effectiveness. The purpose of this review is to critically examine the experimental conditions of the preclinical background for anti-EGFR drug -cytotoxic agent combinations and to attempt to explain the gap between clinical observations and preclinical data. The epidermal growth factor receptor (EGFR) is present in many cell types and can be considered as one of the best-characterised ligand-receptor systems (Mendelsohn and Baselga, 2006). Epidermal growth factor receptor is a 170-kDa cell surface glycoprotein containing three well-identified domains: an extracellular ligandbinding domain, a hydrophobic membrane-spanning domain and a cytoplasmic portion containing the tyrosine kinase activity. The hyperactivation of EGFR signalling in tumours occurs via independent or combined mechanisms: overexpression of the receptor itself, autocrine overproduction of ligand with mainly EGF and tumour growth factor (TGFa), and EGFR mutations, notably through the variant III that maintains the EGFR signalling pathway in a state of continuous activation. Binding of a growth factor to its receptor initiates organised and oriented biochemical intracellular events. These include the activation of the receptor, a cascade of phosphorylation with different protein kinases and, at the nuclear level, the activation of transcription factors. The effects of EGFR activation on tumour cells are multiple and convergent, thus favouring uncontrolled cell growth with an increase in cell mobility and cell proliferation, a decrease in apoptotic machinery and stimulation of angiogenesis. In the clinic, EGFR overexpression has been associated with chemoresistance, disease progression and poor survival (Baselga, 2002). Considering the set of therapeutic tools targeting EGFR (Castillo et al, 2004), there are two well-identified categories of drugs, with monoclonal antibodies (mAbs) on one hand and tyrosine kinase inhibitors (TKIs) on the other. Both treatment tools have reached a mature stage of clinical development. Current therapeutic applications with anti-EGFR drugs show encouraging clinical results. This is true mainly for combin...

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“…Recent studies reported EGF can inhibit or stimulate Fas-induced apoptosis [14,20,25], and the EGF receptor (EGFR) is frequently upregulated in response to chemotherapy [11,42]. EGF can also modulate TGFb and/ or Fas/FasL expression and activity [14,40,45].…”

Section: Introductionmentioning

confidence: 99%

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Joyner

Aboulafia

Damron

et al. 2008

Clin Orthop Relat Res

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Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFb, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFb and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFb1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

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Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non–small cell lung cancer cells

Cited by 86 publications

References 49 publications

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

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