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
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.
Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.
PLoS One. 2015 Mar 17;10(3):e0119832. doi: 10.1371/journal.pone.0119832. eCollection 2015.
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.
旁路信号（如MET和AXL）的激活已被确定为表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药的一种可能机制。由于各种癌蛋白的成熟和稳定性依赖于热休克蛋白90（HSP90），我们研究了一种新开发的非格尔德霉素类HSP90抑制剂AUY922对具有MET和AXL介导耐药性的肺癌细胞的影响。我们通过长期暴露于浓度递增的吉非替尼和厄洛替尼（分别为HCC827/GR和HCC827/ER），建立了携带EGFR基因外显子19缺失突变的HCC827细胞耐药株。HCC827/GR耐药由MET激活介导，而AXL激活导致HCC827/ER细胞耐药。AUY922处理有效抑制了两种耐药细胞株的增殖并诱导细胞死亡。因此，EGFR、MET和AXL的下调导致Akt激活减少。在基因转染的LK2细胞中证实了AUY922对每种受体的抑制作用。AUY922在含有HCC827/GR和HCC827/ER细胞的异种移植小鼠模型中也有效控制了肿瘤生长。此外，AUY922减少了两种耐药细胞的侵袭和迁移。因此，我们的研究结果表明，AUY922是治疗肺癌中MET和AXL介导的EGFR-TKI耐药的一种有前景的治疗选择。
