The Role of Epithelial–Mesenchymal Transition and IGF-1R Expression in Prediction of Gefitinib Activity as the Second-Line Treatment for Advanced Nonsmall-Cell Lung Cancer

Chen, Bei; Xiao, Feng; Li, Baofeng; Xie, Bo; Zhou, Juan; Zheng, Jihua; Zhang, Weimin

doi:10.3109/07357907.2013.820315

Cited by 15 publications

(15 citation statements)

References 28 publications

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“…Hence, EMT status may be a valuable marker for predicting EGFR-TKI treatment response in the EGFR wild-type group. This hypothesis has been investigated and confirmed in several in vitro and in vivo studies (36)(37)(38)(42)(43)(44). One example is a retrospective analysis of 99 patients with wild-type EGFR where EMT status was evaluated using a combined IHC-score for E-cadherin, N-cadherin, fibronectin and vimentin and showing that EMT status is a predictive factor for experiencing an objective response or stable disease during EGFR-TKI treatment (epithelial 23.5%, mesenchymal 2.4%) (38).…”

Section: Treatment Response In Egfr Wild-type Patientsmentioning

confidence: 99%

“…The presence of EGFR mutations and an epithelial phenotype is correlated (37,38). Ren et al found that among 99 mutated patients 57.7% appeared with epithelial or intermediary epithelial-to-mesenchymal phenotype, whereas only 25.77% was clearly mesenchymal (38).…”

Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

“…Ren et al found that among 99 mutated patients 57.7% appeared with epithelial or intermediary epithelial-to-mesenchymal phenotype, whereas only 25.77% was clearly mesenchymal (38). 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).…”

Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

“…Since EGFR mutated tumors often have an epithelial phenotype (37,38), EGFR-driven cancer may have an inherent tendency towards being epithelial. The subgroup of EGFR wild-type patients responding to EGFR-TKIs exploits another type of EGFR-dependency that may also be linked to an epithelial phenotype.…”

Section: Treatment Response In Egfr Wild-type Patientsmentioning

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: Treatment Response In Egfr Wild-type Patientsmentioning

confidence: 99%

Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

Section: Intrinsic Resistance In Egfr Mutated Patientsmentioning

confidence: 99%

Section: Treatment Response In Egfr Wild-type Patientsmentioning

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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“…13,14 It was also reported that mesenchymal markers were more frequently expressed in rebiopsy samples of patients with acquired resistance to EGFR-TKI. 15,16 Moreover, in the limited clinical data, [17][18][19] patients with epithelial markers showed a trend to have a higher response rate (RR) or longer progression-free survival (PFS) with EGFR-TKI therapy. Importantly, targeting EMT may reverse or prevent acquisition of therapeutic resistance to EGFR inhibitors, as illustrated by one study in which restoration of an epithelial phenotype in NSCLC cell lines restored sensitivity to gefitinib.…”

mentioning

confidence: 99%

Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR

Ren

Wang

et al. 2014

Int. J. Cancer

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Epithelial-to-mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p 5 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p 5 0.011), longer progression-free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild-type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR-TKI therapy in this population.Tailored therapy based on biomarker analysis has entered reality of lung cancer treatment. Patients with EGFR-activated mutation or ALK/ROS1 fusion gain significant benefit from targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or ALK inhibitors. However, only a minority of patients express these markers, with EGFR

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Fluorinated thiazolidinol drives autophagic cell death in pancreatic cancer cells via AMPK activation and perturbation of critical sentinels of oncogenic signaling

Kumar

Kommalapati

Jerald

et al. 2021

Chemico-Biological Interactions

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The Role of Epithelial–Mesenchymal Transition and IGF-1R Expression in Prediction of Gefitinib Activity as the Second-Line Treatment for Advanced Nonsmall-Cell Lung Cancer

Abstract: EMT is correlated with efficacy of gefitinib as the second-line treatment for NSCLC, and combined detection of EMT and IGF-1R may be used as new predictors besides EGFR mutation, especially for patients with WT EGFR.

Cited by 15 publications

References 28 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

Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR

Fluorinated thiazolidinol drives autophagic cell death in pancreatic cancer cells via AMPK activation and perturbation of critical sentinels of oncogenic signaling

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