The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models
The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models
复制标题
DOI：
10.1158/1078-0432.ccr-16-0569
复制
发表时间：
2016-11-15
影响因子：
11.5
通讯作者：
Rivera, Victor M.
中科院分区：
文献类型：
--
作者：
Zhang, Sen;Anjum, Rana;Rivera, Victor M.
目的：携带ALK基因重排(ALK(+))的非小细胞肺癌(NSCLC)通常通过ALK的继发性耐药突变或脑内疾病进展而对第一代间变性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂(TKI)Crizotinib产生耐药性。还发现了对第二代ALK、TKIs、ceritinib和alectinib产生耐药性的突变。在这里，我们报告了新一代ALK TKI brigatinib的结构和首次全面的临床前评估。实验设计：通过激酶筛选来评估brigatinib的选择性。使用工程细胞系和肿瘤来源的细胞系比较了ALK TKI的细胞和体内活性。结果：Brigatinib对ALK和ROS1有很强的抑制作用，对250多种酶具有高度的选择性。在一组ALK(+)细胞系中，Brigatinib抑制天然ALK(IC_(50)，10nmol/L)的效力是Crizotinib的12倍。Brigatinib在ALK(+)肿瘤皮下或脑内移植的小鼠中也观察到了优越的疗效。在细胞测试中，Brigatinib对所有17个二次ALK突变体保持了相当的活性，并且在临床可达到的浓度下，与crizotinib、ceritinib和alectinib相比，显示出更好的抑制特性。Brigatinib是唯一对最顽固的ALK耐药突变G1202R保持实质性活性的TKI。结论：Brigatinib是一种高效、高选择性的ALK抑制剂。这些发现为在临床试验中使用Brigatinib治疗ALK(+)、Crizotinib耐药的NSCLC患者观察到的有前景的活性提供了分子基础。(C)2016年AACR。
Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. (C)2016 AACR.