The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Jakobsen, Kristine Raaby; Demuth, Christina; Sørensen, Boe Sandahl; Nielsen, Anders Lade

doi:10.21037/tlcr.2016.04.07

Cited by 90 publications

(87 citation statements)

References 75 publications

(96 reference statements)

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“…Collectively, the results of the present study confirmed that, even if mechanisms of resistance to first-, second-, third- EGFR-TKIs are heterogeneous, EMT represents a common characteristic of resistant tumors [28, 29]. In this model, EMT is activated together with the Hh pathway in all resistant tumors.…”

Section: Discussionsupporting

confidence: 82%

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

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PurposeThe aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors.Experimental designWe developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib).ResultsHCC827-derived xenografts and with acquired resistance to EGFR-inhibitors were sensitive to the sequential use of first-, second- and third-generation EGFR-TKIs. Continuous EGFR inhibition of first-generation resistant tumors by sequential treatment with afatinib plus/minus cetuximab, followed by osimertinib, represented an effective therapeutic strategy in this model. Whereas T790M resistance mutation was not detected, a major mechanism of acquired resistance was the activation of components of the Hedgehog (Hh) pathway. This phenomenon was accompanied by epithelial-to-mesenchymal transition. Cell lines established in vitro from gefitinib-, or afatinib- or osimertinib-resistant tumors showed metastatic properties and maintained EGFR-TKIs resistance in vitro, that was reverted by the combined blockade of Hh, with the selective SMO inhibitor sonidegib, and EGFR.ConclusionsEGFR-mutant NSCLC can benefit from continuous treatment with EGFR-inhibitors, indepenently from mechanisms of resistance. In a complex and heterogenous scenario, Hh showed an important role in mediating resistance to EGFR-inhibitors through the induction of mesenchymal properties.

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Section: Discussionsupporting

confidence: 82%

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

et al. 2017

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“…ZEB1 is zinc finger E-box binding homeobox 1 that involved in the progression of EMT in various kinds of cancers [36]. Furthermore, the EMT process was described by lacking cell-cell adhesion, which has an association of migratory and invasive features [37].…”

Section: Discussionmentioning

confidence: 99%

Up-regulated Linc00472 suppresses development of lung cancer cell via inhibition of MiR-196b-5p

Mao¹,

Zhou²,

Li³

et al. 2019

Bioscience, Biotechnology, and Biochemistry

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The role of linc00472 in lung cancer (LC) has been rarely reported. We aimed to study the role of linc00472 in LC progression. Expressions of linc00472 and miR-196b-5p in LC cell lines were measured by qRT-PCR. The targeting relationship between linc00472 and miR-196b-5p was determined by Starbase and dual-luciferase reporter. The viability, migration, invasion, and apoptosis of LC cells were determined using CCK-8 assay, scratch test, transwell assay, and flow cytometry, respectively. The levels of epithelial-to-mesenchymal transition (EMT)-related proteins and apoptosis-related proteins in LC cells were determined by western blot. Downregulated linc00472 was observed in five LC cell lines. Linc00472 overexpression suppressed viability, migration, invasion and EMT process, but elevated apoptotic rate in LC cells. MiR-196b-5p mimic promoted viability, migration, invasion, and EMT process, but decreased apoptotic rate, which was reversed by up-regulated linc00472. Linc00472 functioned as a cancer suppressor via negatively regulating miR-196b-5p of LC cells.

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“…11,[30][31][32] Indeed, elucidating how EMT could be inhibited or reversed in NSCLC would enable the development of new strategies aimed at optimizing the efficacy of EGFR-TKI to improve the therapeutic outcome. Due to the reversibility of EMT, pharmaceutical options targeting EMT are under investigation.…”

Section: Discussionmentioning

confidence: 99%

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Lou

Yan

Zhu

et al. 2017

Biological & Pharmaceutical Bulletin

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Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.

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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

Cited by 90 publications

References 75 publications

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Up-regulated Linc00472 suppresses development of lung cancer cell via inhibition of MiR-196b-5p

Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

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