Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK activation pathway

Ph, Lu; Tc, Kuo; Chang, Kin-Chow; Ch, Chang; Chu, Chia-Yu

doi:10.1111/j.1365-2133.2010.10038.x

Cited by 18 publications

(16 citation statements)

References 26 publications

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“…The group reversed by cetuximab is only approximately half as large as the group reversed by gefitinib, which is consistent with the lesser degree of EGFR inhibition produced by cetuximab in our model (Fig. 2), as well as with possible off target effects of gefitinib because of its inhibition of multiple kinases (49, 50). …”

Section: Resultssupporting

confidence: 89%

Protein Expression Signatures for Inhibition of Epidermal Growth Factor Receptor-mediated Signaling

Myers¹,

Manning²,

Coffey³

et al. 2012

Molecular & Cellular Proteomics

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Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be complicated by artifactual changes in phosphorylation caused by uncontrolled preanalytical variables, particularly in the analysis of tissue specimens. We asked whether changes in protein expression, which are more stable and easily analyzed, could reflect network stimulation and inhibition. We employed this approach to analyze stimulation and inhibition of the epidermal growth factor receptor (EGFR) by EGF and selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating A431 cells, EGF-stimulated cells, and cells co-treated with the EGFR inhibitors cetuximab or gefitinib identified groups of differentially expressed proteins. Comparisons of these protein groups identified 13 proteins whose EGF-induced expression changes were reversed by both EGFR inhibitors. Targeted multiple reaction monitoring analysis verified differential expression of 12 of these proteins, which comprise a candidate EGFR inhibition signature. We then tested these 12 proteins by multiple reaction monitoring analysis in three other models: 1) a comparison of DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in formalin-fixed, paraffin-embedded mouse xenograft DiFi and HCT116 tumors, and 3) in tissue biopsies from a patient with the gastric hyperproliferative disorder Ménétrier's disease who was treated with cetuximab. Of the proteins in the candidate signature, a core group, including c-Jun, Jagged-1, and Claudin 4, were decreased by EGFR inhibitors in all three models. Although the goal of these studies was not to validate a clinically useful EGFR inhibition signature, the results confirm the hypothesis that clinically used EGFR inhibitors generate characteristic protein expression changes. This work further outlines a prototypical approach to derive and test protein expression signatures for drug action on signaling networks.

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Section: Resultssupporting

confidence: 89%

Protein Expression Signatures for Inhibition of Epidermal Growth Factor Receptor-mediated Signaling

Myers¹,

Manning²,

Coffey³

et al. 2012

Molecular & Cellular Proteomics

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“…p38 MAPK pathways are known as stress response signals and interact with the PI3K/Akt/mTOR pathway [36]. Recently, it was reported that keratinocyte apoptosis induced by gefitinib, which is a selective EGFR tyrosine kinase inhibitor, is mediated by the JNK activation pathway [42]. This study did not reproduce the results of that report; therefore, the mechanisms underlying everolimus-induced keratinocyte apoptosis may differ from those underlying gefitinib-induced apoptosis.…”

Section: Discussionmentioning

confidence: 78%

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Yamamoto

Uda

Mukai

et al. 2013

J Exp Clin Cancer Res

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BackgroundMammalian target of rapamycin (mTOR) inhibitors are associated with dermatological adverse events. The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 (STAT3) protein and the dermatological adverse events associated with the mTOR inhibitor everolimus.MethodsWe evaluated the effects of STAT3 activity and related signal transduction activities on everolimus-induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST-8 assay, and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis. Apoptosis was evaluated using an imaging cytometric assay.ResultsThe cell growth inhibitory effects of everolimus were enhanced by stattic or STA-21, which are selective inhibitors of STAT3, treatment in HaCaT cells, although such effects were not observed in Caki-1 and HepG2 cells. Phosphorylation at tyrosine 705 of STAT3 was decreased by treatment with everolimus in a dose-dependent manner in HaCaT cells; in contrast, phosphorylation at serine 727 was not decreased by everolimus, but slightly increased. Furthermore, we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of STAT3 in HaCaT cells resisted the cytostatic activity of everolimus.ConclusionsThese findings suggest that STAT3 activity may be a biomarker of everolimus-induced dermatological toxicity.

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“…In summary, we find that clinically available small molecule EGFR inhibitors targeting the tyrosine kinase site of the EGFR receptor, including gefitinib and lapatinib, are effective analgesics in mice for inflammatory and neuropathic pain. These drugs are routinely given to non-small cell lung cancer patients (37,38) to inhibit tumor growth, but have not been systematically studied for their role in pain management. Since we find that EREG is the primary endogenous activator of EGFR-related pain hypersensitivity, our data suggest that an effective treatment strategy may be the selective inhibition of EREG over other endogenous EGFR ligands.…”

Section: Ereg Pain Hypersensitivity Is Mediated By a Signal Transductmentioning

confidence: 99%

Epiregulin and EGFR interactions are involved in pain processing

Martin¹,

Smith²,

Khoutorsky³

et al. 2017

Journal of Clinical Investigation

118

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Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK activation pathway

Abstract: Gefitinib can induce keratinocyte apoptosis through an EGFR-independent JNK activation pathway.

Cited by 18 publications

References 26 publications

Protein Expression Signatures for Inhibition of Epidermal Growth Factor Receptor-mediated Signaling

Protein Expression Signatures for Inhibition of Epidermal Growth Factor Receptor-mediated Signaling

Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition

Epiregulin and EGFR interactions are involved in pain processing

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