title: The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Infarinato
authors.affiliation: Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Krytska
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hannah T
authors.initials: HT
authors.lastname: Ryles
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Renata
authors.initials: R
authors.lastname: Sano
authors.affiliation: Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Szigety
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Nathan V
authors.initials: NV
authors.lastname: Lee
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development, San Diego, California.
authors.forename: Tod
authors.initials: T
authors.lastname: Smeal
authors.affiliation: Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. mosse@chop.edu.
authors.forename: Yael P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib