Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias.

Cancer Cell
Authors
Keywords
Abstract

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.

Year of Publication
2019
Journal
Cancer Cell
Volume
35
Issue
4
Pages
664-676.e7
Date Published
2019 04 15
ISSN
1878-3686
DOI
10.1016/j.ccell.2019.03.004
PubMed ID
30991026
PubMed Central ID
PMC6541931
Links
Grant list
R01 CA193651 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States