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

Autor: Ganesh Umapathy, Yann Jamin, B. Witek, Simon P. Robinson, Jikui Guan, H. Wan, Damini Chand, Laura Danielson, Kristina Ruuth, T. W. Johnson, T. Smeal, Tommy Martinsson, Ruth H. Palmer, Elizabeth R. Tucker, Louis Chesler, A. El Wakil, B. Hallberg
Rok vydání: 2016
Předmět:
0301 basic medicine
Pyridines
Aminopyridines
lcsh:Medicine
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology)
Molecular Biology
Microbiology
Biochemistry or Biopharmacy)
Medicine (miscellaneous)
Mouse models
PC12 Cells
Neuroblastoma
Immunology and Microbiology (miscellaneous)
hemic and lymphatic diseases
MYCN
Anaplastic Lymphoma Kinase
PF-06463922
Clinical Trials as Topic
Mice
Inbred BALB C
N-Myc Proto-Oncogene Protein
Lorlatinib
Kinase
3. Good health
Research Article
lcsh:RB1-214
medicine.drug
Lactams
medicine.drug_class
Lactams
Macrocyclic
Neuroscience (miscellaneous)
Mice
Nude
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Crizotinib
Cell Line
Tumor
lcsh:Pathology
medicine
ROS1
Animals
Protein Kinase Inhibitors
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi)
molekylärbiologi
mikrobiologi
biokemi eller biofarmaci)
Cell Proliferation
Cell growth
lcsh:R
Receptor Protein-Tyrosine Kinases
Dd
medicine.disease
Xenograft Model Antitumor Assays
Molecular biology
Rats
ALK inhibitor
030104 developmental biology
ALK
Mutation
Pyrazoles
Zdroj: Europe PubMed Central
Disease Models & Mechanisms, Vol 9, Iss 9, Pp 941-952 (2016)
Disease Models & Mechanisms
ISSN: 1754-8411
1754-8403
DOI: 10.1242/dmm.024448
Popis: 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-ALKF1174L/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.
Summary: Our results suggest that PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.
Databáze: OpenAIRE
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