PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

Cancer Cell. 2015 Jul 13;28(1):70-81. doi: 10.1016/j.ccell.2015.05.010. Epub 2015 Jul 2.

Abstract

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Lactams, Macrocyclic / administration & dosage*
  • Lactams, Macrocyclic / pharmacology
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Lactams, Macrocyclic
  • Protein Kinase Inhibitors
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • lorlatinib