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

Yun Jung Choi; Seon Ye Kim; Kwang Sup So; In-Jeoung Baek; Woo Sung Kim; Se Hoon Choi; Jae Cheol Lee; Trever G Bivona; Jin Kyung Rho; Chang-Min Choi

doi:10.1371/journal.pone.0119832

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

PLoS One. 2015 Mar 17;10(3):e0119832. doi: 10.1371/journal.pone.0119832. eCollection 2015.

Authors

Affiliations

¹ Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea; Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
² Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
³ Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
⁴ Thoracic and Cardiovascular Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
⁵ Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
⁶ Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America.
⁷ Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea; Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axl Receptor Tyrosine Kinase
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors*
Erlotinib Hydrochloride / pharmacology
Erlotinib Hydrochloride / therapeutic use
Female
Gefitinib
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Isoxazoles / pharmacology*
Lung Neoplasms / genetics*
Mice, SCID
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-met / genetics
Quinazolines / pharmacology
Quinazolines / therapeutic use
Receptor Protein-Tyrosine Kinases / genetics
Resorcinols / pharmacology*
Xenograft Model Antitumor Assays

Substances

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
HSP90 Heat-Shock Proteins
Isoxazoles
Proto-Oncogene Proteins
Quinazolines
Resorcinols
Erlotinib Hydrochloride
ErbB Receptors
Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases
Gefitinib
Axl Receptor Tyrosine Kinase

Grants and funding

J.K. Rho had been awarded a grant of the National Research Foundation of Korea (NRF, 2013R1A1A2005112) and S.H. Choi had been awarded a grant of the Asan Institute for Life Sciences (2014-597). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.