title: The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.
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.
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Guan
authors.affiliation: Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Tucker
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Wan
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Chand
authors.affiliation: Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
authors.forename: L S
authors.initials: LS
authors.lastname: Danielson
authors.affiliation: 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.
authors.forename: K
authors.initials: K
authors.lastname: Ruuth
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: El Wakil
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Witek
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Jamin
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Umapathy
authors.affiliation: Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Johnson
authors.affiliation: La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
authors.forename: T
authors.initials: T
authors.lastname: Smeal
authors.affiliation: Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Martinsson
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Chesler
authors.affiliation: 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.
authors.forename: R H
authors.initials: RH
authors.lastname: Palmer
authors.affiliation: 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.
authors.forename: B
authors.identifier: 0000-0003-2032-2616
authors.initials: B
authors.lastname: Hallberg
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D000077547:Crizotinib; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D000071447:N-Myc Proto-Oncogene Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D000071447:N-Myc Proto-Oncogene Protein; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib
keywords: ALK; Lorlatinib; MYCN; Mouse models; Neuroblastoma; PF-06463922