The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study

Boch, Christian; Kollmeier, Jens; Roth, Andreas; Stephan-Falkenau, Susann; Misch, Daniel; Grüning, Wolfram; Bauer, Torsten T.; Mairinger, Thomas

doi:10.1136/bmjopen-2013-002560

Cited by 131 publications

(139 citation statements)

References 31 publications

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“…A previous study on TKI-sensitive NSCLC indicated that a mutation in the EGFR tyrosine kinase domain is responsible for activating various anti-apoptotic signaling pathways (14). An EGFR mutation may be detected in 43-89% of patients with lung cancer; mutations on exons 19 and 21 are the most common (15). These mutations have been observed to confer increased cell sensitivity to TKIs, including to icotinib (3).…”

Section: Discussionmentioning

confidence: 99%

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Zhai¹,

Zhang²,

Kang

et al. 2017

Oncology Letters

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Abstract. The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

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Section: Discussionmentioning

confidence: 99%

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Zhai¹,

Zhang²,

Kang

et al. 2017

Oncology Letters

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“…These results have led to a consensus that the presence of EGFR mutations is a strong predictor of TKI treatment response and various associations and working groups, internationally and in Poland, now recommend screening newly diagnosed patients with advanced NSCLC for specific mutations in order to customize the modality of treatment (9,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Despite these, the incidence rates of EGFR mutations are found to vary substantially between different regions and countries (8,10,15). Possible reasons for this discrepancy could be lack of clarity in selection criteria for EGFR-positivity testing, differences in molecular methods employed for screening, and issues with sampling and tissue preservation.…”

Section: Predictors Of Egfr Mutation and Factors Associated With Clinmentioning

confidence: 99%

“…These cause a loss in autoinhibition of the tyrosine kinase and a continually activated state of its kinase function. Deletion in exon 19 and a L858R (leucine to arginine substitution at position 858) substitution in exon 21 comprise approximately 90% of EGFR mutations found in adenocarcinomas of the lung (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Patients with diagnosed mutations in EGFR are referred to as EGFR-positive.…”

Section: Introductionmentioning

confidence: 99%

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

et al. 2017

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Abstract. Targeted therapy of non-small cell lung cancer (NSCLC) patients with mutations in the epidermal growth factor receptor (EGFR) gene has been associated with improved prognosis. However, there is a shortage on data from real-world clinical practice in management of EGFR-positive NSCLC patients in Poland. The present study retrospectively analyzed data from the INSIGHT study to evaluate the incidence and clinical management of EGFR-positive NSCLC in Poland. The authors additionally aimed to identify predictors of the EGFR mutation and factors associated with clinical stage of the tumor at diagnosis. Incidence of EGFR mutations was 11.8% and the most common mutations were a deletion on exon 19 and an L858R substitution on exon 21. Mutations were strongly associated with female gender [male vs. female odds ratio (OR): 0.51; P=0.004] and never having smoked (current/past smoker vs. never smoked OR: 0.16; P<0.001), and advanced clinical stage (stage IV vs. stage I/II OR: 2.89; P=0.029). Patients with EGFR mutation were also observed to have a greater propensity to develop bone metastasis (OR: 11.62; P=0.008). Multivariate regression analysis demonstrated that patients with past or current smoking history or a poor performance on the Eastern Cooperative Oncology Group (ECOG) scale were less likely to have the EGFR mutation. Furthermore, EGFR-positive patients with greater ECOG scores and a tumor other than adenocarcinoma or squamous cell carcinoma were more likely to present advanced tumors. Early screening for EGFR mutation and the use of EGFR-targeting therapies as first-line agents may lead to better prognosis and successful clinical management of EGFR-positive NSCLC patients.

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“…A total of 2 × 106 HCC827, HCC827/ ER, siNEDD4-, or EV-infected HCC827/ER cells were subcutaneously injected into the mouse skin under the left lower quadrants, respectively. When tumor volumes reached about 100-150 mm 3 , these mice were treated with intragastric administration of erlotinib (60 mg/kg) for 2 weeks once a day. Tumor sizes were measured every 3 days.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

Sun

Wang

et al. 2017

Tumour Biol.

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Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors, such as gefitinib and erlotinib, is a critical issue in the treatment of patients with epidermal growth factor receptor mutant-positive non-small-cell lung cancer. Recent evidence suggests that downregulation of gene of phosphatase and tensin homolog deleted on chromosome 10 plays an important role in acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in various types of cancers, including lung cancer. It was reported that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated gene (NEDD4) (also known as NEDD4-1) negatively regulated phosphatase and tensin homolog deleted on chromosome 10 protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder. Whether this process plays a role in epidermal growth factor receptor-tyrosine kinase inhibitors resistance in non-small-cell lung cancer has not been studied extensively. In view of this, we investigated the involvement of NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 in acquired erlotinib resistance with tyrosine kinase inhibitor-sensitive (HCC827) or tyrosine kinase inhibitor-resistant (Erlotinib-resistant HCC827/ER cells which harbored exon 19 deletion. Overexpression of NEDD4 in HCC827/ER cells was detected, and the reverse correlation between NEDD4 and phosphatase and tensin homolog deleted on chromosome 10 expression in these cells was also revealed. In HCC827/ER cells with knockdown of NEDD4, phosphatase and tensin homolog deleted on chromosome 10 and p-Akt expressions were decreased; the sensitivity of HCC827/ER cells to erlotinib was partially restored. Similar results were also observed in vivo. In H1650/ER cells harboring both exon 19 and phosphatase and tensin homolog deleted on chromosome 10 deletion, expression of p-Akt and sensitivity to erlotinib were not affected by simple knockdown of NEDD4 but affected after transfection of phosphatase and tensin homolog deleted on chromosome 10 into H1650/ER cells. Our results demonstrate that NEDD4 may promote the acquired resistance of non-small-cell lung cancer cells to erlotinib by decreasing phosphatase and tensin homolog deleted on chromosome 10 protein expression. Targeted decrease in NEDD4 expression may be a potential therapeutic strategy for tyrosine kinase inhibitor-resistant non-small-cell lung cancer. KeywordsPhosphatase and tensin homolog deleted on chromosome 10 degradation, NEDD4, acquired tyrosine kinase inhibitor resistance, non-small-cell lung cancer Date

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The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study

Cited by 131 publications

References 31 publications

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

Phosphatase and tensin homolog deleted on chromosome 10 degradation induced by NEDD4 promotes acquired erlotinib resistance in non–small-cell lung cancer

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