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Journal of Cancer Research and Clinical Oncology

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24.05.2018 | Original Article – Cancer Research

Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial–mesenchymal transition phenotype

verfasst von: Jing Xu, Xiaoting Zhao, Dengfeng He, Jinghui Wang, Weiying Li, Yinghui Liu, Li Ma, Mei Jiang, Yu Teng, Ziyu Wang, Meng Gu, Jianbin Wu, Yue Wang, Wentao Yue, Shucai Zhang

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 8/2018

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Abstract

Purpose

AZD9291 is an irreversible, small-molecule inhibitor which has potency against mutant EGFR- and T790M-resistant mutation. Despite the encouraging efficacy in clinical, the acquired resistance will finally occur. Further study will need to be done to identify the acquired resistance mechanisms and determine the next treatment.

Methods

We established an AZD9291-resistant cell line (HCC827/AZDR) from parental HCC827 cell line through stepwise pulsed selection of AZD9291. The expression of EGFR and its downstream pathways were determined by western blot analysis or immunofluorescence assay. The sensitivity to indicated agents were evaluated by MTS.

Results

Compared with parental HCC827 cells, the HCC827/AZDR cells showed high resistance to AZD9291 and other EGFR-TKIs, and exhibited a mesenchymal-like phenotype. Almost complete loss of EGFR expression was observed in HCC827/AZDR cells. But the activation of downstream pathway, MAPK signaling, was found in HCC827/AZDR cells even in the presence of AZD9291. Inhibition of MAPK signaling had no effect on cell viability of HCC827/AZDR and could not reverse AZD9291 resistance because of the subsequent activation of AKT signaling. When treated with the combination of AKT and MAPK inhibitor, HCC827/AZDR showed remarkable growth inhibition.

Conclusions

Loss of EGFR could be proposed as a potential acquired resistance mechanism of AZD9291 in EGFR-mutant NSCLC cells with an EMT phenotype. Despite the loss of EGFR, the activation of MAPK pathway which had crosstalk with AKT pathway could maintain the proliferation and survival of resistant cells. Blocking MAPK and AKT signaling may be a potential therapeutic strategy following AZD9291 resistance.

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Titel: Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial–mesenchymal transition phenotype
verfasst von: Jing Xu
Xiaoting Zhao
Dengfeng He
Jinghui Wang
Weiying Li
Yinghui Liu
Li Ma
Mei Jiang
Yu Teng
Ziyu Wang
Meng Gu
Jianbin Wu
Yue Wang
Wentao Yue
Shucai Zhang
Publikationsdatum: 24.05.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 8/2018
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-018-2668-7

Springer Medizin

Loss of EGFR confers acquired resistance to AZD9291 in an EGFR-mutant non-small cell lung cancer cell line with an epithelial–mesenchymal transition phenotype