MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells.
MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells.
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DOI：
10.1038/oncsis.2017.17
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发表时间：
2017-04-03
期刊：
影响因子：
6.2
通讯作者：
Sorensen BS
中科院分区：
文献类型：
--
作者：
Jakobsen KR;Demuth C;Madsen AT;Hussmann D;Vad-Nielsen J;Nielsen AL;Sorensen BS
Although many epidermal growth factor receptor (EGFR)-mutated lung cancer patients initially benefit from the EGFR-inhibitor erlotinib, all acquire resistance. So far, several mechanisms implicated in resistance have been identified, but the existence of multiple resistance mechanisms in parallel have only been sparsely investigated. In this study, we investigated parallel resistance mechanisms acquired by HCC827, an EGFR-mutated adenocarcinoma cell line dependent on EGFR activity and sensitive to erlotinib. The cell line was treated with erlotinib by stepwise escalation of the drug-concentration and erlotinib-resistant (HCC827ER) cells created. HCC827ER cells depicted a mixed epithelial and mesenchymal phenotype. To clarify potential parallel resistance mechanisms, 14 resistant subclones were established by limited dilution. Interestingly, all HCC827ER subclones harbored either a MET-amplification (6/14) or underwent EMT (8/14), mechanisms both found in previous studies, but not in co-occurrence. Both subclone-types were resistant to erlotinib, but only MET-subclones responded to the MET-inhibitors crizotinib and capmatinib. EMT-subclones on the other hand had markedly increased FGFR1 expression and responded to the FGFR-inhibitor AZD4547, whereas MET-subclones did not. Monitoring gene expression through the development of HCC827ER revealed upregulation of FGFR1 expression as an early response to erlotinib. In addition, FGFR1 expression increased upon short-term erlotinib treatment (48 h) identifying a physiological role immediately after erlotinib exposure. The high FGFR1 expression seen in EMT-subclones was stable even after five passages without erlotinib. Here we show, that parallel resistance mechanisms appear during erlotinib-resistance development in EGFR-mutated NSCLC cells and highlight a role for FGFR1 expression changes as an early response to erlotinib as well as a bypass-signaling mechanism.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
4.6
作者：
Vazquez-Martin, Alejandro;Cufi, Silvia;Oliveras-Ferraros, Cristina;Zenobia Torres-Garcia, Violeta;Corominas-Faja, Bruna;Cuyas, Elisabet;Bonavia, Rosa;Visa, Joana;Martin-Castillo, Begona;Barrajon-Catalan, Enrique;Micol, Vicente;Bosch-Barrera, Joaquim;Menendez, Javier A.
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影响因子：
158.5
作者：
Sequist, L. V.;Soria, J-C;Camidge, D. R.
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Camidge, D. R.
DOI：
10.1158/1078-0432.ccr-13-3060
发表时间：
2014-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Wynes MW;Hinz TK;Gao D;Martini M;Marek LA;Ware KE;Edwards MG;Böhm D;Perner S;Helfrich BA;Dziadziuszko R;Jassem J;Wojtylak S;Sejda A;Gozgit JM;Bunn PA Jr;Camidge DR;Tan AC;Hirsch FR;Heasley LE
通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
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