Oncotarget

Research Papers:

In vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET

Sachiko Arai, Kenji Kita, Azusa Tanimoto, Shinji Takeuchi, Koji Fukuda, Hiroshi Sato and Seiji Yano _

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Oncotarget. 2017; 8:73766-73773. https://doi.org/10.18632/oncotarget.17900

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Abstract

Sachiko Arai1,*, Kenji Kita1,*, Azusa Tanimoto1, Shinji Takeuchi1, Koji Fukuda1, Hiroshi Sato2 and Seiji Yano1

1Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

2Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

*These authors contributed equally to this work

Correspondence to:

Seiji Yano, email: syano@staff.kanazawa-u.ac.jp

Keywords: RET fusion, lung cancer, alectinib, pleural carcinomatosis, NCOA4-RET

Received: February 20, 2017     Accepted: March 19, 2017     Published: May 16, 2017

ABSTRACT

Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1–2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET. However, the activity of alectinib with respect to RET with other fusion partners is unknown. In the present study, we investigated the effects of alectinib on NCOA4-RET fusion-positive tumor cells in vitro and in vivo. Alectinib inhibited the viability of NCOA4-RET-positive EHMES-10 cells, as well as CCDC6-RET-positive LC-2/ad and TPC-1 cells. This was achieved via inhibition of the phosphorylation of RET and induction of apoptosis. Moreover, alectinib suppressed the production of thoracic tumors and pleural effusions in an orthotopic intrathoracic inoculation model of EHMES-10 cells. In vivo imaging of an orthotopically inoculated EHMES-10 cell model also revealed that alectinib could rescue pleural carcinomatosis. These results suggest that alectinib may be a promising RET inhibitor against tumors positive for not only KIF5B-RET and CCDC6-RET, but also NCOA4-RET.


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