Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

Kogita,Akihiro; Togashi,Yosuke; Hayashi,Hidetoshi; Banno,Eri; Terashima,Masato; De Velasco,Marco A.; Sakai,Kazuko; Fujita,Yoshihiko; Tomida,Shuta; Takeyama,Yoshifumi; Okuno,Kiyotaka; Nakagawa,Kazuhiko; Nishio,Kazuto

doi:10.3892/ijo.2014.2797

Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer

Authors:
- Akihiro Kogita
- Yosuke Togashi
- Hidetoshi Hayashi
- Eri Banno
- Masato Terashima
- Marco A. De Velasco
- Kazuko Sakai
- Yoshihiko Fujita
- Shuta Tomida
- Yoshifumi Takeyama
- Kiyotaka Okuno
- Kazuhiko Nakagawa
- Kazuto Nishio
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Affiliations: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka 589-8511, Japan, Department of Surgery, Kinki University Faculty of Medicine, Osaka 589-8511, Japan, Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka 589-8511, Japan
Published online on: December 15, 2014 https://doi.org/10.3892/ijo.2014.2797
Pages: 1025-1030

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Abstract

Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

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