Abstract
Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined. Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527-38. ©2016 AACR.
Highlights
Activating gene rearrangements in anaplastic lymphoma kinase (ALKþ), first identified in patients with anaplastic large-cell lymphoma (ALCL), have been shown to be oncogenic drivers in patients with non–small cell lung cancer (NSCLC; 3%–7%) and other cancers [1]
Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations
Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALKþ, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials
Summary
Activating gene rearrangements in anaplastic lymphoma kinase (ALKþ), first identified in patients with anaplastic large-cell lymphoma (ALCL), have been shown to be oncogenic drivers in patients with non–small cell lung cancer (NSCLC; 3%–7%) and other cancers [1]. The ALK/ROS1/MET tyrosine kinase inhibitor (TKI) crizotinib is highly active in ALKþ NSCLC, inducing responses in 60% to 74% of patients [2, 3]. ALK-dependent mechanisms of resistance, observed in approximately 30% of patients, include the acquisition of secondary mutations in ALK that interfere with crizotinib binding and/or amplification of the ALK fusion gene. ALK-independent mechanisms, for example, via activation of EGFR-, IGF-1R-, or KIT-mediated signaling pathways, have been shown to contribute to crizotinib resistance [4]
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