Epithelial‐to‐mesenchymal transition in the context of epidermal growth factor receptor inhibition in non‐small‐cell lung cancer

Abstract

The identification of oncogenic driver mutations in non-small-cell lung cancer (NSCLC) has led to the development of targeted drugs. Tyrosine kinase inhibitors (TKIs) directed against the epidermal growth factor receptor (EGFR) target lung tumours bearing EGFR-activating mutations. This new therapeutic strategy has greatly improved tumour response rates. However, drug resistance invariably occurs during TKI-based treatment. Epithelial-to-mesenchymal transition (EMT) is one of the resistance mechanisms identified in EGFR-mutated NSCLC treated with TKIs. In this review we gather together the most important findings on this phenomenon in relation to cancer stem cells and cancer epigenetics. We also outline the correlation between the effects of stromal factors from the microenvironment, the transcription factors activated, the epigenetic changes in chromatin, and the evolution of cellular behaviour. Notably, EMT has already been shown to be the link between benign lung diseases such as chronic obstructive pulmonary disease and lung carcinogenesis. The various mechanisms of acquired resistance to EGFR-TKIs are also briefly described to provide background information on EMT. Our extensive review of the scientific literature serves to highlight the cellular and molecular events that lead to the onset of EMT in NSCLC cells treated with EGFR-TKIs. Finally, we put forward a hypothesis to explain why, in some cases, EMT rather than other known mechanisms is involved in resistance to TKIs.

α5‐nAChR contributes to epithelial‐mesenchymal transition and metastasis by regulating Jab1/Csn5 signalling in lung cancer

“…A remarkable proportion of cases are only detected in the advanced stage when the tumour has already metastasized to other organs, resulting in poor clinical prognosis . Epithelial‐mesenchymal transition (EMT) is generally considered to be the key progression promoting the metastasis of lung cancer . Thus, elucidating the molecular mechanism of EMT is of great significance in preventing lung cancer metastasis and progression.…”

The permissive role of TCTP in PM2.5/NNK-induced epithelial–mesenchymal transition in lung cells

“…Cancer stem cell (CSC) plasticity and cancer dissemination in the metastatic process were associated with EMT [10]. The phenotypic changes that characterized the transition from CSCs to differentiated cancer cells involved a process occurring in EMT [11]. It has been demonstrated that EMT was the link between benign lung diseases and lung carcinogenesis.…”

“…It has been demonstrated that EMT was the link between benign lung diseases and lung carcinogenesis. Thus, EMT played a central role in the development of lung cancer [11].…”

Epithelial-to-mesenchymal transition and EGFR status in NSCLC: the role of vimentin expression

“…Although vimentin has long been known to play a role in carcinogenesis, its potential involvement in resistance to cancer therapies has also been described, especially EGFR-directed tyrosine kinase inhibitors (TKIs) [2]. Vimentin is a type III intermediate filament protein constitutively expressed in mesenchymal cells (e.g.…”

“…A total of 76 cases were also listed in the RMRP (56 certain, 19 probable/possible and 1 non-MM). The RMRP, established in 1993, is part of a national mesothelioma registry (ReNaM, Registro Nazionale Mesoteliomi) organized as a network of regional registries which follow the same procedures for classifying the available diagnostic evidence [2,3].…”