Research Papers:

Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial–mesenchymal transition is critical in conquering ALK-positive lung cancer

Shinji Nakamichi, Masahiro Seike _, Akihiko Miyanaga, Mika Chiba, Fenfei Zou, Akiko Takahashi, Arimi Ishikawa, Shinobu Kunugi, Rintaro Noro, Kaoru Kubota and Akihiko Gemma

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Oncotarget. 2018; 9:27242-27255. https://doi.org/10.18632/oncotarget.25531

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Shinji Nakamichi1, Masahiro Seike1, Akihiko Miyanaga1, Mika Chiba1, Fenfei Zou1, Akiko Takahashi1, Arimi Ishikawa2, Shinobu Kunugi2, Rintaro Noro1, Kaoru Kubota1 and Akihiko Gemma1

1Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan

2Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan

Correspondence to:

Masahiro Seike, email: [email protected]

Keywords: ALK; lung cancer; resistance; EMT; AXL

Received: August 16, 2017    Accepted: May 14, 2018    Published: June 05, 2018


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.

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