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

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, including T-lymphoblastic, hypodiploid B-lymphoblastic, and acute myeloid leukemias, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3dependent protein ubiquitination and degradation. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 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. SIGNIFICANCEThe intensification of asparaginase-based therapy has improved outcomes for several subtypes of acute leukemia, but the development of treatment resistance has a poor prognosis. We hypothesized, from the concept of synthetic lethality, that gain-of-fitness alterations in drugresistant cells had conferred a survival advantage that could be exploited therapeutically. We found a synthetic lethal interaction between activation of Wnt-dependent stabilization of proteins (Wnt/STOP) and asparaginase in acute leukemias resistant to this enzyme. Inhibition of the alpha isoform of GSK3 was sufficient to phenocopy this effect, and the combination of GSK3-selective inhibitors and asparaginase had marked therapeutic activity against leukemias resistant to monotherapy with either agent. These data indicate that drug-drug synthetic lethal interactions can improve the therapeutic index of cancer therapy.

Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

“…However, to the best of our knowledge, no applications of it on the engineering of ASNase have been reported in the scientific literature. Interestingly, there have been some reported instances of its use on the elucidation of the genetic markers responsible for ASNase-therapy resistance in certain ALL cell lineages, which has led to promising new treatment proposals (Butler et al, 2017; Ding et al, 2017; Hinze et al, 2018; Montaño et al, 2018).…”

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas

“…Given the clinically aggressive behavior of UCSs and limited treatment options [64], exploring targeting HER2 in this subset of HER2-amplified UCSs may be warranted [65]. Likewise, therapeutic strategies based on synthetic lethality to target tumors with FBXW7 mutations have emerged [66,67]; given the relatively high frequency of FBXW7 mutations in UCSs (30%), further studies testing this potential treatment strategy might be entertained.…”

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.…”