Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma

Invest New Drugs. 2020 Jun;38(3):599-609. doi: 10.1007/s10637-019-00802-7. Epub 2019 Jun 8.

Abstract

ALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin's lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous process with multiple underlying mechanisms, including ALK gene amplification, ALK kinase domain mutation, and the activation of various bypass signaling pathways. To overcome resistance, multiple promising next-generation ALK kinase inhibitors and rational combinatorial strategies are being developed. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired crizotinib resistance by exposing a highly sensitive NPM-ALK-positive ALCL cell line to increasing doses of crizotinib until resistance emerged. We found that the NPM-ALK mutation was selected under intermediate-concentration drug stress in resistant clones, accompanied by activation of the IGF-1R pathway. In the crizotinib-resistant ALCL cell model, the IGF-1R pathway was activated, and combined ALK/IGF-1R inhibition improved therapeutic efficacy. Furthermore, we also detected the NPM-ALK G1269A mutation, which had previously been demonstrated to result in decreased affinity for crizotinib, in the resistant cell model. Although crizotinib was ineffective against cells harboring the NPM-ALK G1269A mutation, five structurally different ALK inhibitors, alectinib, ceritinib, TAE684, ASP3026 and AP26113, maintained activity against the resistant cells. Thus, we have shown that second-generation ALK tyrosine kinase inhibitors or IGF-1R inhibitors are effective in treating crizotinib-resistant tumors.

Keywords: ALCL; ALK; Crizotinib; Drug resistance; IGF-1R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / genetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Crizotinib / pharmacology*
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / drug therapy*
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Mutation / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor, IGF Type 1 / genetics*
  • Signal Transduction / genetics

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Crizotinib
  • p80(NPM-ALK) protein
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, IGF Type 1