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

• Published in: PloS one 2015-03, Vol.10 (3), p.e0119832-e0119832
• Main Authors: Choi, Yun Jung, Kim, Seon Ye, So, Kwang Sup, Baek, In-Jeoung, Kim, Woo Sung, Choi, Se Hoon, Lee, Jae Cheol, Bivona, Trever G, Rho, Jin Kyung, Choi, Chang-Min
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; Angiogenesis; Animal models; Animals; Apoptosis; Axl protein; Biotechnology; Cancer; Cancer cells; Cancer therapies; Cell cycle; Cell death; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Survival; Clinical trials; Clonal deletion; Critical care; Drug dosages; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Female; Gefitinib; Geldanamycin; Gene amplification; Gene deletion; Growth factors; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; Immunoglobulins; Isoxazoles - pharmacology; Kinases; Life sciences; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Medicine; Metastasis; Mice, SCID; Mutation; Oncology; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-met - genetics; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Resorcinols - pharmacology; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119832

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.