Epidermal growth factor receptor: mechanisms of activation and signalling

Jorissen, Robert N.; Walker, Francesca; Pouliot, Normand; Garrett, T.P.J.; Ward, Colin W.; Burgess, Antony W.

doi:10.1016/s0014-4827(02)00098-8

Cited by 1,360 publications

(1,107 citation statements)

References 271 publications

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“…In addition, phosphorylation of MAPK in cells harboring mutants G735S and G796S was also observed, which may contribute to the increased colony formation and invasive potential conferred by these mutants. Of the three oncogenic mutations, cells expressing the mutant E804G were phosphorylated at the highest levels (at Y992, Y1068 and Y1173), which presumably leads to signal transduction and downstream activation of mitogenic and/or anti-apoptotic pathways (Hanahan and Weinberg, 2000;Jorissen et al, 2003;Shao et al, 2003;Sordella et al, 2004;Citri and Yarden, 2006). However, we did not observe the expected extent of activation for MAPK and/or STAT3 with cells that expressed mutant E804G.…”

Section: Discussioncontrasting

confidence: 60%

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

et al. 2008

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While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.

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Section: Discussioncontrasting

confidence: 60%

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

et al. 2008

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“…The activated EGFR kinase phosphorylates tyrosines in the EGFR C-terminal, initiates signaling cascades, and stimulates cell growth and differentiation ( Figure 6). 13,169,170 …”

Section: Egfr Targeted Therapy Approachesmentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…K-RAS mutations) [8,9]. 4 Two major intracellular signaling pathways activated by EGFR, the PI3K/AKT/mTOR and the RAS/RAF/MAPK cascades, have a central role in controlling cell survival and modulating cell growth and proliferation [10]. These pathways represent potential novel therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

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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Epidermal growth factor receptor: mechanisms of activation and signalling

Cited by 1,360 publications

References 271 publications

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

Molecular pathology of lung cancer: key to personalized medicine

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

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