BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway

• Published in: Blood 2021-12, Vol.138 (23), p.2383-2395
• Main Authors: Butler, Miriam, van Ingen Schenau, Dorette S., Yu, Jiangyan, Jenni, Silvia, Dobay, Maria P., Hagelaar, Rico, Vervoort, Britt M.T., Tee, Trisha M., Hoff, Fieke W., Meijerink, Jules P., Kornblau, Steven M., Bornhauser, Beat, Bourquin, Jean-Pierre, Kuiper, Roland P., van der Meer, Laurens T., van Leeuwen, Frank N.
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenine - therapeutic use; Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Agammaglobulinaemia Tyrosine Kinase - metabolism; Amino Acids - metabolism; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Asparaginase - pharmacology; Asparaginase - therapeutic use; Cell Line, Tumor; Humans; Lymphoid Neoplasia; Mice; Piperidines - pharmacology; Piperidines - therapeutic use; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Signal Transduction - drug effects
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021011787

Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc–mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453. •CRISPR/Cas9 kinome screen identifies genes involved in ASNase sensitivity.•Ibrutinib synergizes with ASNase by inhibiting the amino acid response pathway via c-Myc– mediated regulation of GCN2. [Display omitted]