Resistance to asparaginase is a common clinical problem, whose biologic basis is poorly
understood. We hypothesized, from the concept of synthetic lethality, that gain-of-fitness
alterations in drug-resistant cells had conferred a survival advantage that could
be exploited therapeutically. Using a genome-wide CRISPR/Cas9 screen in T-ALL, we
found that negative regulators of Wnt signaling were selectively depleted upon treatment
with asparaginase. Wnt pathway activation induced profound 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 GSK3-dependent protein ubiquitination and proteasomal
degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3
was sufficient to phenocopy synthetic lethality with asparaginase, and pharmacologic
GSK3 alpha inhibition profoundly sensitized drug-resistant leukemias to asparaginase
in vitro and in vivo. These results demonstrate that synthetic lethal drug-drug interactions
can improve the therapeutic index of cancer therapy.
