Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians

Wang, Yongsheng; Schmid-Bindert, Gerald; Zhou, Caicun

doi:10.1177/1758834011427927

Cited by 90 publications

(61 citation statements)

References 47 publications

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“…The predictive value of EMT status in EGFR mutated patients was also investigated, but no significant correlation between an epithelial phenotype and EGFR-TKI response was identified in the group of EGFR mutated patients (37,38). EGFR mutated patients in general experience a good relative response to EGFR-TKI with only 30% of patients not responding (14,15). This taken together with the tendency to an epithelial phenotype among the EGFR mutated patients suggests that the presence of an EGFR mutation overrules any influence of EMT status.…”

Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

“…So far, some resistance mechanisms have been discovered including the T790M secondary mutation in EGFR, MET amplification, FGFR overexpression, IGF1R overexpression, transition to small cell lung carcinoma, gain of cancer stem-cell features, and epithelial to mesenchymal transition (EMT), but much still needs to be revealed (9)(10)(11)(12)(13). Up to 30% of the patients with EGFR mutations experience no objective response to EGFR-TKIs and hence appear as intrinsic resistant (14,15). Some patients without EGFR mutations initially benefit from erlotinib with experience of objective response (approx.…”

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confidence: 99%

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The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and resistance to lung cancer therapy Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The 5-year survival remains at 10-15% despite advances in treatment options.Erlotinib, a TKI targeting EGFR, was initially explored as a second-line treatment in NSCLC patients progressing on standard chemotherapy. Survival was prolonged compared to placebo (1). However, erlotinib was soon discovered to be especially efficient in patients with a mutation in the tyrosine kinase domain of EGFR. These patients are nowThe role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer Correspondence to: Anders Lade Nielsen. Department of Biomedicine, Bartholin Building, Aarhus University, DK-8000, Aarhus C, Denmark.Email: aln@biomed.au.dk.Abstract: Inhibition of the epidermal growth factor receptor (EGFR) is an important strategy when treating non-small cell lung cancer (NSCLC) patients. However, intrinsic resistance or development of resistance during the course of treatment constitutes a major challenge. The knowledge on EGFRdirected tyrosine kinase inhibitors (TKIs) and their biological effect keeps increasing. Within the group of patients with EGFR mutations some benefit to a much higher degree than others, and for patients lacking EGFR mutations a subset experience an effect. Up to 70% of patients with EGFR mutations and 10-20% of patients without EGFR mutations initially respond to the EGFR-TKI erlotinib, but there is a severe absence of good prognostic markers. Despite initial effect, all patients acquire resistance to EGFR-TKIs.Multiple mechanisms have implications in resistance development, but much is still to be explored. Epithelial to mesenchymal transition (EMT) is a transcriptionally regulated phenotypic shift rendering cells more invasive and migratory. Within the EMT process lays a need for external or internal stimuli to give rise to changes in central signaling pathways. Expression of mesenchymal markers correlates to a bad prognosis and an inferior response to EGFR-TKIs in NSCLC due to the contribution to a resistant phenotype. A deeper understanding of the role of EMT in NSCLC and especially in EGFR-TKI resistance-development constitute one opportunity to improve the benefit of TKI treatment for the individual patient. Many scientific studies have linked the EMT process to EGFR-TKI resistance in NSCLC and our aim is to review the role of EMT in both intrinsic and acquired resistance to EGFR-TKIs.Keywords: Epidermal growth factor receptor (EGFR); epithelial to mesenchymal transition (EMT); non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI)

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Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

mentioning

confidence: 99%

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen

Demuth

Sørensen³

et al. 2016

Transl. Lung Cancer Res.

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“…16 The idea that EGF may play a role in water balance was previously suggested by Gow and Phillips, 17 because they showed that EGF infusion in sheep resulted in brisk diuresis and natriuresis. Therefore, we used erlotinib, a Food and Drug Administration (FDA) -approved EGFR inhibitor, 18,19 to study the underlying pathways affected by EGF inhibition in water balance.…”

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confidence: 99%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

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Nephrogenic diabetes insipidus (NDI) is caused by impairment of vasopressin (VP) receptor type 2 signaling. Because potential therapies for NDI that target the canonical VP/cAMP/protein kinase A pathway have so far proven ineffective, alternative strategies for modulating aquaporin 2 (AQP2) trafficking have been sought. Successful identification of compounds by our high-throughput chemical screening assay prompted us to determine whether EGF receptor (EGFR) inhibitors stimulate AQP2 trafficking and reduce urine output. Erlotinib, a selective EGFR inhibitor, enhanced AQP2 apical membrane expression in collecting duct principal cells and reduced urine volume by 45% after 5 days of treatment in mice with lithiuminduced NDI. Similar to VP, erlotinib increased exocytosis and decreased endocytosis in LLC-PK1 cells, resulting in a significant increase in AQP2 membrane accumulation. Erlotinib increased phosphorylation of AQP2 at Ser-256 and Ser-269 and decreased phosphorylation at Ser-261 in a dose-dependent manner. However, unlike VP, the effect of erlotinib was independent of cAMP, cGMP, and protein kinase A. Conversely, EGF reduced VP-induced AQP2 Ser-256 phosphorylation, suggesting crosstalk between VP and EGF in AQP2 trafficking and a role of EGF in water homeostasis. These results reveal a novel pathway that contributes to the regulation of AQP2-mediated water reabsorption and suggest new potential therapeutic strategies for NDI treatment.

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“…Gefitinib and erlotinib are small molecule tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), extensively studied in patients with NSCLC (27,28). Although the inhibitors are also used in pretreated and non-selected patients on the basis of EGFR mutational status (11,(29)(30)(31), these molecules have elective indication for EGFR mutation-positive patients as front-line treatment (32,33).…”

Section: Activity Of Gefitinib and Erlotinibmentioning

confidence: 99%

Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer

et al. 2015

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Abstract. Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib. IntroductionThe 'elderly' patient with lung cancer treated with cytotoxic chemotherapy has been the subject of several studies that have assumed international importance due to sample size, methodological rigor and impact on clinical practice. Confirmed by evidence-based medicine, these important trials have led to the definition of therapeutic standards validated in this patient subset: The ELVIS study showed the superiority of vinorelbine over placebo (1); the MILES study showed a similar effectiveness between single-agent vinorelbine or gemcitabine, and single-agent efficacy over the combination of vinorelbine plus gemcitabine (2); the MILES 2P study showed better survival for cisplatin plus gemcitabine compared with cisplatin plus vinorelbine (3); the IFCT-0501 study showed survival benefits with carboplatin plus weekly paclitaxel compared with vinorelbine or gemcitabine monotherapy (4); another study showed improved survival with platinum-based adjuvant chemotherapy (5); and in a phase II trial involving elderly patients with advanced-stage small cell lung cancer, the weekly regimen of gemcitabine and docetaxel demonstrated no advantage over standard therapy (6).The last decade of research in this field has witnessed the emergence of molecular-targeted therapies as an essential element for the treatment of patients with non-small cell lung cancer (NSCLC) (7). The studies on the activity of these novel therapies in the elderly patient with NSCLC are few (8,9), comprising a more fragmented and less numerous casuistry tha...

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Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians

Cited by 90 publications

References 47 publications

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer

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