Erlotinib

Steins, Martin; Thomas, Michael; Geißler, Michael

doi:10.1007/978-3-642-54490-3_6

Cited by 14 publications

(8 citation statements)

References 70 publications

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“…Data from mice having mutant EGFR further support the role of EGFR in AngII associated cardiac remodeling 12 . However, whether an EGFR inhibitor such as erlotinib utilized for human cancer treatments 13 has therapeutic potential against hypertensive vascular remodeling remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Role of Epidermal Growth Factor Receptor and Endoplasmic Reticulum Stress in Vascular Remodeling Induced by Angiotensin II

et al. 2015

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The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage appear to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by metalloprotease ADAM17, and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with Erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells was also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension.

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Section: Introductionmentioning

confidence: 99%

Role of Epidermal Growth Factor Receptor and Endoplasmic Reticulum Stress in Vascular Remodeling Induced by Angiotensin II

et al. 2015

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“…TKIs such as erlotinib are effective for treatment of advanced NSCLC tumors harboring EGFR-activating mutations. However, many patients treated with erlotinib develop resistance to the targeted molecular therapy (Tang et al, 2013;Steins et al, 2014). PKC isozymes have been recognized as key effectors of known oncogenes implicated in drug resistance such as c-MET, KRAS, and TGF-b (Kermorgant et al, 2004;Sakaguchi et al, 2004;Symonds et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the EGFR gene, particularly deletion of exon 19 and L858R mutation in exon 21, occur in 10-50% of NSCLC patients (Gazdar, 2009;Cooper et al, 2013). Small molecule tyrosine-kinase inhibitors (TKIs) that reversibly inhibit EGFR at the ATP pocket domain, such as erlotinib and gefitinib, currently represent the first line of therapy for EGFR-mutated NSCLC patients (Antonicelli et al, 2013;Steins et al, 2014). Although these therapies are initially efficacious, ultimately most patients develop resistance.…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Abera

Kazanietz

2015

Mol Pharmacol

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Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymallike morphology driven by transforming growth factor-b signaling. We found that H1650-M3 cells display remarkable PKCa upregulation and PKCd downregulation. Notably, silencing PKCa from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-tomesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCa RNA interference depletion and PKCd restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCa in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCd expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCa upregulation in H1650-M3 cells is driven by transforming growth factor-b. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCa as a potential target for lung cancer treatment.

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“…For example, since the oncogene ERBB2 ( HER2 ) is amplified in subgroups of glioblastoma and, stomach, uterine, bladder, and lung cancers, responsiveness to HER2-targeted therapy may or may not be analogous to that of HER2 -amplified breast cancer [ 9 , 10 ]. Similarly, erlotinib, an effective inhibitor of the actively mutated epidermal growth factor receptor (EGFR), originally approved for the treatment of advanced pancreatic cancer, has now shown efficacy for non-small cell lung and various other cancers [ 11 ]. Here, to more rapidly make such preliminary determinations, we designed and developed a comprehensive web-based assessment tool, “CANcer-specific Evaluation System” (CANES), for exhaustive biomarker evaluation that: (i) employs repositories across 2,134 whole transcriptome datasets, from 94,147 biological samples (cell lines and normal and cancerous tissues), representing 18 tumor types; (ii) performs the initial steps of evaluating single and/or multi-genes as biomarker candidates; and (iii) uses various classification methods to support diagnostic or prognostic assessment of genes, as well as miRNAs, as biomarkers, yielding a “pan-cancer” summary view of the evaluation of each individual biomarker.…”

Section: Introductionmentioning

confidence: 99%

CANcer-specific Evaluation System (CANES): a high-accuracy platform, for preclinical single/multi-biomarker discovery

et al. 2017

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The recent creation of enormous, cancer-related “Big Data” public depositories represents a powerful means for understanding tumorigenesis. However, a consistently accurate system for clinically evaluating single/multi-biomarkers remains lacking, and it has been asserted that oft-failed clinical advancement of biomarkers occurs within the very early stages of biomarker assessment. To address these challenges, we developed a clinically testable, web-based tool, CANcer-specific single/multi-biomarker Evaluation System (CANES), to evaluate biomarker effectiveness, across 2,134 whole transcriptome datasets, from 94,147 biological samples (from 18 tumor types). For user-provided single/multi-biomarkers, CANES evaluates the performance of single/multi-biomarker candidates, based on four classification methods, support vector machine, random forest, neural networks, and classification and regression trees. In addition, CANES offers several advantages over earlier analysis tools, including: 1) survival analysis; 2) evaluation of mature miRNAs as markers for user-defined diagnostic or prognostic purposes; and 3) provision of a “pan-cancer” summary view, based on each single marker. We believe that such “landscape” evaluation of single/multi-biomarkers, for diagnostic therapeutic/prognostic decision-making, will be highly valuable for the discovery and “repurposing” of existing biomarkers (and their specific targeted therapies), leading to improved patient therapeutic stratification, a key component of targeted therapy success for the avoidance of therapy resistance.

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Erlotinib

Cited by 14 publications

References 70 publications

Role of Epidermal Growth Factor Receptor and Endoplasmic Reticulum Stress in Vascular Remodeling Induced by Angiotensin II

Role of Epidermal Growth Factor Receptor and Endoplasmic Reticulum Stress in Vascular Remodeling Induced by Angiotensin II

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

CANcer-specific Evaluation System (CANES): a high-accuracy platform, for preclinical single/multi-biomarker discovery

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