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

Miriam Butler, Dorette S van Ingen Schenau, Jiangyan Yu, Silvia Jenni, Maria P Dobay, Rico Hagelaar, Britt M T Vervoort, Trisha M Tee, Fieke W Hoff, Jules P Meijerink, Steven M Kornblau, Beat Bornhauser, Jean-Pierre Bourquin, Roland P Kuiper, Laurens T van der Meer, Frank N van Leeuwen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)2383-2395
Aantal pagina's13
TijdschriftBlood
Volume138
Nummer van het tijdschrift23
DOI's
StatusGepubliceerd - 9 dec. 2021

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