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

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 5; pp. 1023 - 1028
• Main Authors: Kodama, Tatsushi, Hasegawa, Masami, Takanashi, Kenji, Sakurai, Yuji, Kondoh, Osamu, Sakamoto, Hiroshi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2014; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - secondary; Caco-2 Cells; Cancer Research; Carbazoles - blood; Carbazoles - pharmacokinetics; Carbazoles - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Humans; Luciferases - genetics; Luciferases - metabolism; Luminescent Measurements - methods; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical sciences; Medicine; Medicine & Public Health; Mice, Nude; Mice, SCID; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neurology; Oncogene Proteins, Fusion - antagonists & inhibitors; Oncogene Proteins, Fusion - metabolism; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperidines - blood; Piperidines - pharmacokinetics; Piperidines - pharmacology; Pneumology; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Rats; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Tissue Distribution; Tumors; Tumors of the nervous system. Phacomatoses; Tumors of the respiratory system and mediastinum; Xenograft Model Antitumor Assays; ALK; Alectinib; Brain metastases; NSCLC; ALK inhibitor; Antineoplastic agent; Lung disease; Nervous system diseases; Tyrosine kinase inhibitor; Respiratory disease; Brain cancer; Lung cancer; Malignant tumor; non-small cell lung carcinoma; Cerebral metastasis; Biological activity; Cerebral disorder; C-Onc gene; Central nervous system disease; Bronchus disease; Models; Anaplastic lymphoma kinase; Protooncogene; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2578-6

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 14 C-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.