NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922

Oncotarget. 2015 Mar 20;6(8):5720-34. doi: 10.18632/oncotarget.3122.

Abstract

ALK is involved in the onset of several tumors. Crizotinib (XalkoriTM), a potent ALK inhibitor, represents the current front-line treatment for ALK+ NSCLC and shows great clinical efficacy. However, resistant disease often develops after initial response. ASP3026 is a novel second-generation ALK inhibitor with activity on crizotinib-resistant ALK-L1196M gatekeeper mutant. As resistance is likely to be a relevant hurdle for any drug, we sought to determine the resistance profile of ASP3026 in the context of NPM/ALK+ ALCL. We selected six ASP3026-resistant cell lines by culturing human ALCL cells in the presence of increasing concentrations of drug. The established resistant cell lines carry several point mutations in the ALK kinase domain (G1128S, C1156F, I1171N/T, F1174I, N1178H, E1210K and C1156F/D1203N were the most frequent) that are shown to confer resistance to ASP3026 in the Ba/F3 cell model. All mutants were profiled for cross-resistance against a panel of clinically relevant inhibitors including ceritinib, alectinib, crizotinib, AP26113 and PF-06463922. Finally, a genetically heterogeneous ASP3026-resistant cell line was exposed to second-line treatment simulations with all inhibitors. The population evolved according to relative sensitivity of its mutant subclones to the various drugs. Compound PF-06463922 did not allow the outgrowth of any resistant clone, at non-toxic doses.

Keywords: ASP3026; NPM/ALK; PF-06463922; inhibitor; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Apoptosis / drug effects
  • CHO Cells
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cricetulus
  • Humans
  • Lactams, Macrocyclic / chemistry
  • Lactams, Macrocyclic / pharmacology*
  • Lymphoma, Large-Cell, Anaplastic / drug therapy*
  • Lymphoma, Large-Cell, Anaplastic / enzymology
  • Lymphoma, Large-Cell, Anaplastic / genetics
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Models, Molecular
  • Mutation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • ASP3026
  • Lactams, Macrocyclic
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Sulfones
  • Triazines
  • nucleophosmin
  • p80(NPM-ALK) protein
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • lorlatinib