IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma

Blood. 2020 Oct 1;136(14):1657-1669. doi: 10.1182/blood.2019003793.

Abstract

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • CRISPR-Cas Systems
  • Cell Line
  • Crizotinib / pharmacology*
  • Crizotinib / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • Gene Editing
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Interleukin-10 Receptor alpha Subunit / genetics*
  • Interleukin-10 Receptor alpha Subunit / metabolism
  • Lymphoma, Large-Cell, Anaplastic / drug therapy
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / metabolism
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Models, Biological
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Interleukin-10 Receptor alpha Subunit
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Crizotinib
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases