The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

Autor:	Guan J; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden., Tucker ER; Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK., Wan H; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden., Chand D; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden., Danielson LS; Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK., Ruuth K; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden Department of Molecular Biology, Building 6L, Umeå University, Umeå 901 87, Sweden., El Wakil A; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden Department of Molecular Biology, Building 6L, Umeå University, Umeå 901 87, Sweden., Witek B; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden Department of Molecular Biology, Building 6L, Umeå University, Umeå 901 87, Sweden., Jamin Y; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK., Umapathy G; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden., Robinson SP; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK., Johnson TW; La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Smeal T; La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA., Martinsson T; Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden., Chesler L; Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK louis.chesler@icr.ac.uk ruth.palmer@gu.se bengt.hallberg@gu.se., Palmer RH; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden louis.chesler@icr.ac.uk ruth.palmer@gu.se bengt.hallberg@gu.se., Hallberg B; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden louis.chesler@icr.ac.uk ruth.palmer@gu.se bengt.hallberg@gu.se.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2016 Sep 01; Vol. 9 (9), pp. 941-52. Date of Electronic Publication: 2016 Jul 07.
DOI:	10.1242/dmm.024448
Abstrakt:	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.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu