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, E. R., Wan, H., Chand, D., Danielson, L. S., Ruuth, Kristina, El Wakil, A., Witek, B., Jamin, Y., Umapathy, G., Robinson, S. P., Johnson, T. W., Smeal, T., Martinsson, T., Chesler, L., Palmer, R. H., Hallberg, B., Guan, J., Tucker, E. R., Wan, H., Chand, D., Danielson, L. S., Ruuth, Kristina, El Wakil, A., Witek, B., Jamin, Y., Umapathy, G., Robinson, S. P., Johnson, T. W., Smeal, T., Martinsson, T., Chesler, L., Palmer, R. H., and Hallberg, B.
- 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.
- Published
- 2016
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