Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors

被引:187
作者
Lovly, Christine M. [1 ]
Heuckmann, Johannes M. [3 ,4 ]
de Stanchina, Elisa [5 ]
Chen, Heidi [2 ]
Thomas, Roman K. [3 ,4 ,6 ,7 ]
Liang, Chris [8 ]
Pao, William [1 ]
机构
[1] Vanderbilt Univ, Dept Med, Nashville, TN USA
[2] Vanderbilt Univ, Dept Biostat, Nashville, TN USA
[3] Max Planck Gesell, Klaus Joachim Zulich Labs, Max Planck Inst Neurol Res, Cologne, Germany
[4] Univ Cologne, Fac Med, Cologne, Germany
[5] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Facil, New York, NY USA
[6] Univ Cologne, Dept Internal Med, Cologne, Germany
[7] Univ Cologne, Ctr Integrated Oncol Koln Bonn, Cologne, Germany
[8] Xcovery Inc, W Palm Beach, FL USA
关键词
ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; LUNG-CANCER; QUANTITATIVE-ANALYSIS; ACTIVATING MUTATIONS; EXPERIMENTAL-MODELS; ANTITUMOR-ACTIVITY; C-MET; RECEPTOR; IDENTIFICATION;
D O I
10.1158/0008-5472.CAN-10-3879
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Aberrant forms of the anaplastic lymphoma kinase (ALK) have been implicated in the pathogenesis of multiple human cancers, where ALK represents a rational therapeutic target in these settings. In this study, we report the identification and biological characterization of X-376 and X-396, two potent and highly specific ALK small molecule tyrosine kinase inhibitors (TKIs). In Ambit kinome screens, cell growth inhibition studies, and surrogate kinase assays, X-376 and X-396 were more potent inhibitors of ALK but less potent inhibitors of MET compared to PF-02341066 (PF-1066), an ALK/MET dual TKI currently in clinical trials. Both X-376 and X-396 displayed potent antitumor activity in vivo with favorable pharmacokinetic and toxicity profiles. Similar levels of drug sensitivity were displayed by the three most common ALK fusion proteins in lung cancer (EML4-ALK variants E13;A20, E20;A20, and E6b;A20) as well as a KIF5B-ALK fusion protein. Moreover, X-396 could potently inhibit ALK kinases engineered with two point mutations associated with acquired resistance to PF-1066, L1196M, and C1156Y, when engineered into an E13;A20 fusion variant. Finally, X-396 displayed synergistic growth inhibitory activity when combined with the mTOR inhibitor rapamycin. Our findings offer preclinical proof-of-concept for use of these novel agents to improve therapeutic outcomes of patients with mutant ALK-driven malignancies. Cancer Res; 71(14); 4920-31. (C) 2011 AACR.
引用
收藏
页码:4920 / 4931
页数:12
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