EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling

Shen, Jiwei; Meng, Yuting; Wang, Kunlun; Gao, Minghuan; Du, Jianan; Wang, Junfang; Li, Zengqiang; Zuo, Daiying; Wu, Yingliang

doi:10.1016/j.cellsig.2022.110264

Cited by 16 publications

(17 citation statements)

References 47 publications

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“…Rearrangement of the anaplastic lymphoma kinase gene ( ALK ) has been identified in 5%–6% of younger NSCLC patients ( 20 ). Overexpression of ALK in A549 cells can induce epithelial–mesenchymal transition (EMT), and increase migration and invasion, phenomena that are correlated with the upregulation of signal transducer and activator of transcriptions 3 (STAT3) ( 21 ). Many NSCLC patients with an ALK mutation develop drug resistance after taking drugs for a few years.…”

Section: The Biological Features Of Lung Cancermentioning

confidence: 99%

Current treatments for non-small cell lung cancer

et al. 2022

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Despite improved methods of diagnosis and the development of different treatments, mortality from lung cancer remains surprisingly high. Non-small cell lung cancer (NSCLC) accounts for the large majority of lung cancer cases. Therefore, it is important to review current methods of diagnosis and treatments of NSCLC in the clinic and preclinic. In this review, we describe, as a guide for clinicians, current diagnostic methods and therapies (such as chemotherapy, chemoradiotherapy, targeted therapy, antiangiogenic therapy, immunotherapy, and combination therapy) for NSCLC.

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Section: The Biological Features Of Lung Cancermentioning

confidence: 99%

Current treatments for non-small cell lung cancer

et al. 2022

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“…iii) Epithelial-mesenchymal transition; the transformation of tumor epithelial cells to mesenchymal cells increases the ability of tumor cells to invade and metastasize (87). In patients with NSCLC EML4-ALK-targeted drug resistance, the expression of the mesenchymal marker vimentin was increased, and that of the epithelial marker E-cadherin was decreased, suggesting that epithelial-mesenchymal transition may be involved in the drug resistance response (88)(89)(90). In order to overcome the drug resistance of tumor cells, it is currently possible to strengthen the combination of EML4-ALK-targeted and other antitumor drugs, such as the EGFR inhibitor erlotinib, cyclin-dependent kinase inhibitor, and riboxy and heat shock protein 90 inhibitors (91)(92)(93).…”

Section: Targeted Therapy For Eml4-alkmentioning

confidence: 99%

EML4‑ALK fusion gene in non‑small cell lung cancer (Review)

Lei

Shi

et al. 2022

Oncol Lett

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Non-small cell lung cancer (NSCLC) is a malignant tumor with a high morbidity and mortality rate that is a threat to human health. With the development of molecular targeted research, breakthroughs have been made on the molecular mechanism of lung cancer. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene is one of the most important pathogenic driver genes of NSCLC discovered thus far. Four generations of targeted drugs for EML4-ALK have been developed, with patients benefiting significantly from these drugs. Therefore, EML4-ALK has become a research hotspot in NSCLC. The aim of the present study is to introduce the current research progress of EML4-ALK and its association with NSCLC. Contents 1. Introduction 2. EML4-ALK fusion gene 3. Clinical features of EML4-ALK in NSCLC 4. EML4-ALK detection method 5.

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“…Meanwhile, Shen et al (2022) have shown that EML4-ALK V3 G1202R mutation can promote ceritinib resistance through activation of epithelial-to-mesenchymal transition (EMT) via STAT3 upregulation and consequent expression of its downstream target, the Slug transcription factor. A combination of HJC0152, a STAT3 inhibitor, and ceritinib was able to reverse the EMT phenotype and promote apoptosis in drug-resistant EML4-ALK V3 cells [ 55 ]. Hence, the JAK/STAT pathway appears particularly relevant to cells expressing EML4-ALK V3.…”

Section: Targeting Alk-dependent Signalling Pathwaysmentioning

confidence: 99%

“…For instance, the ALK F1174V missense mutation confers resistance to ceritinib but sensitivity to alectinib, whereas conversely the ALK I1171S mutation leads to resistance to alectinib but sensitivity to ceritinib [ 53 , 54 ]. Meanwhile, an ALK F1245C mutation promotes resistance to the first-generation ALK inhibitor, crizotinib, while G1202R is the most common mutation observed in tumours resistant to second generation ALK TKIs [ 52 , 55 ]. Hence, characterization of the ALK sequence following development of resistance to one ALK TKI would facilitate selection of the most suitable subsequent treatment.…”

Section: Introductionmentioning

confidence: 99%

Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer

Papageorgiou

Pashley

O’Regan

et al. 2022

Cancers

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EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.

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EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling

Cited by 16 publications

References 47 publications

Current treatments for non-small cell lung cancer

Current treatments for non-small cell lung cancer

EML4‑ALK fusion gene in non‑small cell lung cancer (Review)

Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer

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