IL10RA Modulates Crizotinib Sensitivity in NPM1-ALK-positive Anaplastic Large Cell Lymphoma

Nom de la revue
Nina Prokoph, Nicola Anna Probst, Liam Changwoo Lee, Jack Michael Monahan, Jamie David Matthews, Huan-Chang Liang, Klaas Bahnsen, Ivonne A Montes-Mojarro, Elif Karaca Atabay, Geeta Geeta Sharma, Vikas Malik, Hugo Larose, Sorcha Denise Forde, Stephen Paul Ducray, Cosimo Lobello, Qi Wang, Shi-Lu Luan, Sarka Pospisilova, Carlo B Gambacorti-Passerini, Amos Burke, Shahid Pervez, Andishe Attarbaschi, Andrea Janikova, Helene 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 Brugieres, Birgit Geoerger, Isaia Barbieri, Suzanne D Turner

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 NPM1-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54-90% in clinical trials. However, a subset of patients progress within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide CRISPR activation and knockout screens in ALCL cell lines combined with RNA-seq 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 IL10RA. Elevated IL10RA expression rewires the STAT3 signaling pathway bypassing otherwise critical phosphorylation by NPM1-ALK. IL10RA expression does not correlate with response to standard chemotherapy in pediatric patients suggesting that combination of crizotinib with chemotherapy could prevent ALK-inhibitor resistance-specific relapse. Trials registered as NCT01979536/NCT02034981/UMIN000028075.