1. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.
- Author
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Guan J, Tucker ER, Wan H, Chand D, Danielson LS, Ruuth K, El Wakil A, Witek B, Jamin Y, Umapathy G, Robinson SP, Johnson TW, Smeal T, Martinsson T, Chesler L, Palmer RH, and Hallberg B
- Subjects
- Aminopyridines, Anaplastic Lymphoma Kinase, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Clinical Trials as Topic, Crizotinib, Lactams, Lactams, Macrocyclic pharmacology, Mice, Inbred BALB C, Mice, Nude, Mutation genetics, N-Myc Proto-Oncogene Protein metabolism, Neuroblastoma pathology, PC12 Cells, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Pyrazoles therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Rats, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Xenograft Model Antitumor Assays, Lactams, Macrocyclic therapeutic use, N-Myc Proto-Oncogene Protein antagonists & inhibitors, Neuroblastoma drug therapy, Protein Kinase Inhibitors therapeutic use, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients., Competing Interests: T.W.J. and T.S. are employees and shareholders of Pfizer Inc. The authors declare no other competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
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