Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib

Suda, Kenichi; Tomizawa, Kenji; Fujii, Makiko; Murakami, Hideki; Osada, Hiroyuki; Maehara, Yoshihiko; Yatabe, Yasushi; Sekido, Yoshitaka; Mitsudomi, Tetsuya

doi:10.1097/jto.0b013e318216ee52

Cited by 217 publications

(184 citation statements)

References 31 publications

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“…This is in line with previous work by others showing that EGFR TKI-resistant EGFR-mutant cells with an EMT phenotype were uniformly not dependent on Met kinase. [5][6][7] Collectively, these findings suggest that Met signaling does not have a key role in inducing or maintaining EMT of EGFR-mutant lung cancer cells.…”

Section: Discussionmentioning

confidence: 78%

“…Although the GR cells analyzed here were selected from cell lines in vitro, studies show that some EGFR-mutant lung cancers with acquired TKI resistance display an EMT phenotype in the clinic. [5][6][7][8] Like EGFR-mutant lung cancer, chronic myeloid leukemia, which has the Bcr-Abl fusion gene, 32 and gastrointestinal stromal tumors, which harbors an activating mutation in the c-kit gene, 33 are addicted to constitutively activated tyrosine kinases. Intriguingly, these In this study, we have also uncovered that GR cells have a higher degree of basal autophagy than their parental cells, which endows them with the potential to evade apoptosis and proliferate even under hypoxic conditions in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…4 EGFR-mutated tumors can also acquire resistance to EGFR TKIs through epithelial-tomesenchymal transition (EMT). [5][6][7][8] Furthermore, the AXL receptor tyrosine kinase has been shown to have a key role in EMT-induced drug resistance; 9 however, it remains unclear whether AXL activation invariably occurs in EGFR-mutant carcinoma cells showing an EMT phenotype.…”

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confidence: 99%

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Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFRmutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Sakuma

Matsukuma

Nakamura

et al. 2013

Laboratory Investigation

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“…Entinostat abolishes the deacetylation of histones and accordingly helps keeping chromatin in an active, transcribed form. As E-cadherin transcription is regulated through epigenetics, HDACinhibitors may induce increased E-cadherin transcription and mesenchymal to epithelial transition (73). In addition, entinostat increases the effect of erlotinib in resistant cell lines (36).…”

Section: Drug Mediated Repression Of Emt In Nsclcmentioning

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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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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“…[9][10][11][12] In the EGFR-TKI-sensitive EGFR mutant lung cancer cell line, EMT plays an important role in the primary resistance of erlotinib. 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.…”

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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Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib

Cited by 217 publications

References 31 publications

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells

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

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