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Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib.

Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S, Toyooka S - Cancer Sci. (2015)

Bottom Line: Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs.In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs.This finding may provide clues to overcoming resistance to EGFR-TKIs.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

No MeSH data available.


Related in: MedlinePlus

Epithelial to mesenchymal transition in afatinib-resistant cell lines. (a) HCC827-AR1, -ACR, -AR4, HCC4006-AR1, and -AR2 displayed downregulation of E-cadherin and upregulation of vimentin. (b) Immunofluorescence cytochemistry of E-cadherin and vimentin on HCC827 and its several sublines are shown. HCC827 displayed epithelial phenotype although HCC827-AR1 and ACR displayed mesenchymal phenotype. Scale bars, 10 μm.
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fig02: Epithelial to mesenchymal transition in afatinib-resistant cell lines. (a) HCC827-AR1, -ACR, -AR4, HCC4006-AR1, and -AR2 displayed downregulation of E-cadherin and upregulation of vimentin. (b) Immunofluorescence cytochemistry of E-cadherin and vimentin on HCC827 and its several sublines are shown. HCC827 displayed epithelial phenotype although HCC827-AR1 and ACR displayed mesenchymal phenotype. Scale bars, 10 μm.

Mentions: HCC827-AR1, HCC827-ACR, HCC827-AR4, and all HCC4006 sublines exhibited downregulation of E-cadherin, which is the epithelial marker, and upregulation of vimentin, which is the mesenchymal marker (Fig. 2a,b). ZEB-1, one of the regulators of EMT and a target of the miR-200c, was also expressed in cells with acquired resistance and EMT features. In fact, the expression of miR-200c was downregulated, and the methylation of the promoter regions in miR-200c was observed in these cell lines (Suppl. Fig. S2). Of note, although HCC827-AR2 that was a MET-amplified cell line did not display EMT features, HCC827-ACR, which was derived from HCC827-AR2 by afatinib plus crizotinib exposure, acquired EMT features. For PC-9 and it resistant sublines, antibody array was performed because the mechanisms of resistance to afatinib in PC-9 sublines were not identified with other assays mentioned above. In the result, phospho-stat1 upregulation by afatinib exposure was shown in PC-9 sublines although not shown in parental cell line,


Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib.

Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S, Toyooka S - Cancer Sci. (2015)

Epithelial to mesenchymal transition in afatinib-resistant cell lines. (a) HCC827-AR1, -ACR, -AR4, HCC4006-AR1, and -AR2 displayed downregulation of E-cadherin and upregulation of vimentin. (b) Immunofluorescence cytochemistry of E-cadherin and vimentin on HCC827 and its several sublines are shown. HCC827 displayed epithelial phenotype although HCC827-AR1 and ACR displayed mesenchymal phenotype. Scale bars, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4638008&req=5

fig02: Epithelial to mesenchymal transition in afatinib-resistant cell lines. (a) HCC827-AR1, -ACR, -AR4, HCC4006-AR1, and -AR2 displayed downregulation of E-cadherin and upregulation of vimentin. (b) Immunofluorescence cytochemistry of E-cadherin and vimentin on HCC827 and its several sublines are shown. HCC827 displayed epithelial phenotype although HCC827-AR1 and ACR displayed mesenchymal phenotype. Scale bars, 10 μm.
Mentions: HCC827-AR1, HCC827-ACR, HCC827-AR4, and all HCC4006 sublines exhibited downregulation of E-cadherin, which is the epithelial marker, and upregulation of vimentin, which is the mesenchymal marker (Fig. 2a,b). ZEB-1, one of the regulators of EMT and a target of the miR-200c, was also expressed in cells with acquired resistance and EMT features. In fact, the expression of miR-200c was downregulated, and the methylation of the promoter regions in miR-200c was observed in these cell lines (Suppl. Fig. S2). Of note, although HCC827-AR2 that was a MET-amplified cell line did not display EMT features, HCC827-ACR, which was derived from HCC827-AR2 by afatinib plus crizotinib exposure, acquired EMT features. For PC-9 and it resistant sublines, antibody array was performed because the mechanisms of resistance to afatinib in PC-9 sublines were not identified with other assays mentioned above. In the result, phospho-stat1 upregulation by afatinib exposure was shown in PC-9 sublines although not shown in parental cell line,

Bottom Line: Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs.In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs.This finding may provide clues to overcoming resistance to EGFR-TKIs.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

No MeSH data available.


Related in: MedlinePlus