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

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.

• Authors: Nina Prokoph, Nicola A Probst, Liam C Lee, Jack M Monahan, Jamie D Matthews, Huan-Chang Liang, Klaas Bahnsen, Ivonne A Montes-Mojarro, Elif Karaca-Atabay, Geeta G Sharma, Vikas Malik, Hugo Larose, Sorcha D Forde, Stephen P Ducray, Cosimo Lobello, Qi Wang, Shi-Lu Luan, Šárka Pospíšilová, Carlo Gambacorti-Passerini, G A Amos Burke, Shahid Pervez, Andishe Attarbaschi, Andrea Janíková, Hélène Pacquement, Judith Landman-Parker, Anne Lambilliotte, Gudrun Schleiermacher, Wolfram Klapper, Ralf Jauch, Wilhelm Woessmann, Gilles Vassal, Lukas Kenner, Olaf Merkel, Luca Mologni, Roberto Chiarle, Laurence Brugières, Birgit Geoerger, Isaia Barbieri, Suzanne D Turner
• Journal: Blood (Blood) Vol. 136 Issue 14 Pg. 1657-1669 (10 01 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32573700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• Interleukin-10 Receptor alpha Subunit
• NPM1 protein, human
• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• STAT3 protein, human
• Nucleophosmin
• Crizotinib
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases

Topics

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