AUY922 effectively overcomes MET- and AXL-mediated resistance to EGFR-TKI in lung cancer cells

PloS One
Yun Jung ChoiChang-Min Choi

Abstract

The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promisin...Continue Reading

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Citations

Feb 13, 2018·Oncology Letters·Guoan ZhangWen Cui
May 26, 2018·Cell Death & Disease·Alisha YallowitzNatalia Marchenko
Nov 5, 2019·Frontiers in Oncology·Emily N ArnerRolf A Brekken

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Methods Mentioned

BETA
transfection
flow cytometry
FACS
xenograft
xenografts
transgenic

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