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Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases

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Abstract

Purpose

The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors.

Methods

We established intracranial tumor implantation mouse models of EML4–ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of 14C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell.

Results

Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood–brain barrier penetration.

Conclusions

We established intracranial tumor implantation models of EML4–ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4–ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

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Acknowledgments

We thank T. Mizuno for the establishment of luciferase-expressing cells; A. Nakagawa and F. Sawamura for the in vivo experiments; and T. Shiga and K. Honda for the tissue-staining experiments.

Conflict of interest

All of the authors are employees of Chugai Pharmaceutical Co., Ltd.

Author information

Authors and Affiliations

  1. Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan

    Tatsushi Kodama, Masami Hasegawa, Kenji Takanashi, Yuji Sakurai, Osamu Kondoh & Hiroshi Sakamoto

Authors
  1. Tatsushi Kodama
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  2. Masami Hasegawa
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  3. Kenji Takanashi
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  4. Yuji Sakurai
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  5. Osamu Kondoh
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  6. Hiroshi Sakamoto
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Corresponding author

Correspondence to Hiroshi Sakamoto.

Additional information

Tatsushi Kodama and Masami Hasegawa have contributed equally to this work.

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Kodama, T., Hasegawa, M., Takanashi, K. et al. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol 74, 1023–1028 (2014). https://doi.org/10.1007/s00280-014-2578-6

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  • DOI: https://doi.org/10.1007/s00280-014-2578-6

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