TY - JOUR
T1 - BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway
AU - Butler, Miriam
AU - van Ingen Schenau, Dorette S.
AU - Yu, Jiangyan
AU - Jenni, Silvia
AU - Dobay, Maria P.
AU - Hagelaar, Rico
AU - Vervoort, Britt M.T.
AU - Tee, Trisha M.
AU - Hoff, Fieke W.
AU - Meijerink, Jules P.
AU - Kornblau, Steven M.
AU - Bornhauser, Beat
AU - Bourquin, Jean Pierre
AU - Kuiper, Roland P.
AU - van der Meer, Laurens T.
AU - van Leeuwen, Frank N.
N1 - Funding Information:
This work was supported, in part, by research funding from Dutch Cancer Society (KWF; grant 10072 and grant 11249), a young investigator grant from Radboudumc (M.B.), a short-term European Molecular Biology Organization (EMBO) fellowship (M.B.) (6870, ASTF 626-2016), Swiss National Science Foundation (SNF; grant 310030-182269) (B.B., J.-P.B.), Fondation Panacée, (B.B., J.-P.B.), Stiftung Kinderkrebsforschung Schweiz (B.B., J.-P.B.), and Sophienstiftung (B.B., J.-P.B.).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/12/9
Y1 - 2021/12/9
N2 - 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.
AB - 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.
U2 - 10.1182/blood.2021011787
DO - 10.1182/blood.2021011787
M3 - Article
C2 - 34280258
AN - SCOPUS:85120747537
SN - 0006-4971
VL - 138
SP - 2383
EP - 2395
JO - Blood
JF - Blood
IS - 23
ER -