The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma
The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma
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DOI：
10.1158/2159-8290.cd-15-1056
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发表时间：
2016-01-01
期刊：
影响因子：
28.2
通讯作者：
Mosse, Yael P.
中科院分区：
文献类型：
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作者：
Infarinato, Nicole R.;Park, Jin H.;Mosse, Yael P.
含有间变性淋巴瘤激酶(ALK)激活点突变的神经母细胞瘤对ALK抑制剂Crizotinib具有不同的敏感性，某些突变导致固有的Crizotinib耐药。为了克服这一临床障碍，我们的目标是找到效力更高的抑制剂，可以针对顽固的ALK变体，如F1174L。我们发现，在体外，PF-06463922对碱性磷酸酶变异体具有很高的效力，并且比克里佐替尼更有效地抑制碱性磷酸酶。最重要的是，PF-06463922可以诱导耐药和敏感的神经母细胞瘤异种移植模型的肿瘤完全消退，以及携带耐药的F1174L或F1245C突变的患者来源的异种移植瘤。这些研究表明，PF-06463922具有克服Crizotinib耐药性的潜力，作为一种针对F1174L和F1245C ALK突变的异种移植瘤的单靶向制剂，具有前所未有的活性，同时也在R1275Q异种移植模型中诱导反应。综上所述，这些结果为将PF-06463922转移到临床试验中用于治疗ALK突变的神经母细胞瘤患者提供了理论基础。意义：新一代ALK/ROS1抑制剂PF-06463922在具有原发克里佐替尼耐药的ALK驱动的神经母细胞瘤模型中发挥着无与伦比的活性。我们的生化和体内数据为快速追踪这种药物在复发/难治性ALK突变神经母细胞瘤儿童中的发展提供了临床前基础。(C)2015年AACR。
Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK - mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK - mutated neuroblastoma.SIGNIFICANCE: The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma. (C) 2015 AACR.