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

Abstract

Graphical AbstractHighlights d A genetic screen revealed synthetic lethality of Wnt activation and asparaginase d Wnt signaling induces asparaginase sensitivity by inhibiting protein degradation d GSK3a inhibition phenocopies Wnt-induced sensitization to asparaginase d This combination has potent activity against asparaginaseresistant leukemias SUMMARY 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 GSK3a 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.

Metabolic dependencies and vulnerabilities in leukemia

“…Altogether, these perturbations induce profound antileukemic effects and, as a result, asparaginase treatment contributes significantly to the success of multiagent chemotherapy regimens for ALL (Sallan et al 1983;Clavell et al 1986). Moreover, activation of the Wnt pathway via GSK3-dependent inhibition, could sensitize leukemia cells to asparaginase (Hinze et al 2019).…”

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

“…Also reported as an activator of the WNT signaling pathway160 .DNR, and L-ASP, in multidrug cross-resistance ways 135. These findings and the knowledge of the transcriptional programs-net can be promising for developing strategies to add to conventional antileukemic agents and enhance the effectiveness of AL treatment.…”

“…The lower levels of asparagine lead to a selective sensitivity of leukemic cells to the treatment. However, resistance mechanisms, such as increased asparagine synthetase expression and protein degradation by proteasome, which is a source of asparagine, have been described and are associated with poor prognosis 159,160 . Wnt pathway activation by suppression of NKD2 and LGR6 (negative regulators of Wnt signaling in T‐ALL) or GSK3 depletion/inhibition, sensitized acute leukemia cell lines to asparaginase through the Wnt/Stop signaling, which inhibits protein ubiquitination and, consequently, proteasomal degradation 160 …”

SLC 1A3 contributes to L‐asparaginase resistance in solid tumors

“…However, the expression of ASNS in ALL did not compromise ASNase effectivity (Vander Heiden & DeBerardinis, ), indicating that the ubiquitous activation of the GCN2‐ATF4‐ASNS axis in response to nutrient deprivation might be essential, but not sufficient to induce ASNase resistance. Very recently, protein degradation was proposed to contribute to ASNase resistance in ALL (Hinze et al , ); however, its contribution in the context of solid tumors is not known yet. Here, we described the identification of SLC1A3, an aspartate/glutamate transporter, as a novel contributor to ASNase resistance and metastasis in cancer cells.…”