BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway.
Adenine
/ analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
/ antagonists & inhibitors
Amino Acids
/ metabolism
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Asparaginase
/ pharmacology
Cell Line, Tumor
Humans
Mice
Piperidines
/ pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Signal Transduction
/ drug effects
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
09 12 2021
09 12 2021
Historique:
received:
19
03
2021
accepted:
02
07
2021
pubmed:
20
7
2021
medline:
4
1
2022
entrez:
19
7
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34280258
pii: S0006-4971(21)01372-0
doi: 10.1182/blood.2021011787
pmc: PMC8832462
doi:
Substances chimiques
Amino Acids
0
Antineoplastic Agents
0
Piperidines
0
ibrutinib
1X70OSD4VX
Agammaglobulinaemia Tyrosine Kinase
EC 2.7.10.2
Asparaginase
EC 3.5.1.1
Adenine
JAC85A2161
Banques de données
ClinicalTrials.gov
['NCT02884453']
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2383-2395Informations de copyright
© 2021 by The American Society of Hematology.
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