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


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 promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer.

SUBMITTER: Choi YJ 

PROVIDER: S-EPMC4363657 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Choi Yun Jung YJ   Kim Seon Ye SY   So Kwang Sup KS   Baek In-Jeoung IJ   Kim Woo Sung WS   Choi Se Hoon SH   Lee Jae Cheol JC   Bivona Trever G TG   Rho Jin Kyung JK   Choi Chang-Min CM  

PloS one 20150317 3


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 increa  ...[more]

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