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• W2807677124 abstract "// Shinji Nakamichi 1 , Masahiro Seike 1 , Akihiko Miyanaga 1 , Mika Chiba 1 , Fenfei Zou 1 , Akiko Takahashi 1 , Arimi Ishikawa 2 , Shinobu Kunugi 2 , Rintaro Noro 1 , Kaoru Kubota 1 and Akihiko Gemma 1 1 Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan 2 Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan Correspondence to: Masahiro Seike, email: mseike@nms.ac.jp Keywords: ALK; lung cancer; resistance; EMT; AXL Received: August 16, 2017     Accepted: May 14, 2018     Published: June 05, 2018 ABSTRACT Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non–small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib . Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy." @default.
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• W2807677124 date "2018-06-05" @default.
• W2807677124 modified "2023-10-10" @default.
• W2807677124 title "Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial-mesenchymal transition is critical in conquering ALK-positive lung cancer" @default.
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• W2807677124 doi "https://doi.org/10.18632/oncotarget.25531" @default.
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