Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cañadas, Israel; Rojo, Federico; Taus, Álvaro; Arpí, Oriol; Arumí-Uría, Montserrat; Pijuán, Lara; Menéndez, Sílvia; Zazo, Sandra; Dómine, Manuel; Salido, Marta; Mojal, Sergi; Herreros, Antonio Garcı́a de; Rovira, Ana; Albanell, Joan; Arriola, Edurne

doi:10.1158/1078-0432.ccr-13-1330

Cited by 118 publications

(102 citation statements)

References 34 publications

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“…MET is normally expressed by cells of epithelial origin, while expression of HGF is restricted to cells of mesenchymal origin (70). HGF mediated EMT induces resistance to chemotherapy in SCLC (71), but so far no reports on MET induced EMT and resistance to EGFR-TKIs in NSCLC exist. Upon HGF stimulation, MET induces several biological responses related to invasive cell growth and abnormal MET activation in cancer correlates with poor prognosis.…”

Section: Metmentioning

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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Section: Metmentioning

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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“…Firstly, tumor-infiltrating neutrophils (TINs), the most important 'fertilizers' in the 'soil' (8,15), lose their conventional antitumor characteristics and acquire a pro-tumor phenotype in the presence of transforming growth factor-β (TGF-β) (44). In our previous study, TIN count was revealed to serve as a prognostic factor and to promote epithelial-mesenchymal transition (EMT) in esophageal cancer (45), which may be a key process involved in regulating chemoresistance in malignant tumors (46)(47)(48). However, TIN is not a conventional indicator for detection due to difficulty in its measurement.…”

Section: Discussionmentioning

confidence: 99%

Predictive value of inflammatory indexes on the chemotherapeutic response in patients with unresectable lung cancer: A retrospective study

Sun

et al. 2018

Oncol Lett

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“…In contrast, slower-growing nonneuroendocrine SCLC cells in tumors, such as Notchactive SCLC cells may be inherently more resistant to chemotherapeutics as shown in a GEMM (discussed above) (52) and may help the neuroendocrine cells survive chemotherapy. SCLC cells with a mesenchymal phenotype may also be intrinsically more chemoresistant (68,69). Furthermore, interactions of SCLC cells with their microenvironment, including the extracellular matrix, may promote chemoresistance, although this has not been tested in animal models (70)(71)(72)(73)(74).…”

Section: Chemoresistant Sclcmentioning

confidence: 99%

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

Shue¹,

Lim²,

Sage³

2018

Transl. Lung Cancer Res.

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Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer characterized by its fast growth and aggressive nature. SCLC development is strongly associated with heavy cigarette smoking. In a majority of cases, SCLC tumors have already metastasized to distant sites at the time of first diagnosis. Except in rare cases when tumors are diagnosed early, treatment options are limited and usually consist of several rounds of chemotherapy with cisplatin/ carboplatin and etoposide. While this chemotherapy regimen often results in significant response and tumor shrinkage, relapse is usually quite rapid. A number of excellent reviews have recently discussed the key clinical features of SCLC and the current lack of efficient treatment despite a large number of clinical trials in the past three decades (1-4). New therapeutic approaches, including immunotherapies, are promising but at the time this review is written, there are still no approved targeted therapies for SCLC [reviewed in (5-8)].Here we discuss emerging data in the field on the role of tumor heterogeneity in the growth of SCLC and the response of these tumors to therapy, and how mouse models have been used to identify such tumor heterogeneity and investigate its role. We use the term "intertumoral" heterogeneity to describe how SCLC tumors in patients or mice evolve differently at the genetic and epigenetic level during tumor progression and metastasis. We use the term "intratumoral" heterogeneity to describe the different subpopulations of cells within tumors at any given time; in Abstract: Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth.We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents.A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients.

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Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cited by 118 publications

References 34 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

Predictive value of inflammatory indexes on the chemotherapeutic response in patients with unresectable lung cancer: A retrospective study

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

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