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

Dis Model Mech. 2016 Sep 1;9(9):941-52. doi: 10.1242/dmm.024448. Epub 2016 Jul 7.

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.

Keywords: ALK; Lorlatinib; MYCN; Mouse models; Neuroblastoma; PF-06463922.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clinical Trials as Topic
  • Crizotinib
  • Lactams, Macrocyclic / pharmacology
  • Lactams, Macrocyclic / therapeutic use*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation / genetics
  • N-Myc Proto-Oncogene Protein / antagonists & inhibitors*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • PC12 Cells
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rats
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Lactams, Macrocyclic
  • N-Myc Proto-Oncogene Protein
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • Alk protein, mouse
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • lorlatinib