WNT Activation Mediates Asparaginase Sensitization in ALL

Asparaginase, the enzyme responsible for deamination of the nonessential amino acid asparagine, is a mainstay of treatment regimens for aggressive hematopoietic malignancies. Acute lymphoblastic leukemia (ALL) cells are particularly sensitive to exogenous asparaginase treatment, as they are largely dependent on exogenous asparagine for their survival. However, resistance to asparaginase can develop and is associated with a poor prognosis. Hinze and colleagues sought to identify molecular pathways necessary for ALL cell fitness upon asparaginase treatment. Two of the top hits from a genome-wide CRISPR/Cas9 loss-of-function screen in an asparaginase-resistant T-ALL cell line were NKD2 and LGR6, genes encoding regulators of WNT signaling, suggesting that asparaginase resistance could be reversed by WNT pathway activation. Individual knockdown experiments validated that depletion of either NKD2 or LGR6 increases levels of active β-catenin and sensitizes ALL cells to asparaginase treatment. Small-molecule inhibition of GSK3, a key step in the activation of WNT/β-catenin signaling, also sensitized cells to asparaginase, but this effect was not phenocopied by activation of β-Catenin, the canonical effector of WNT signaling. Instead, WNT pathway activation promoted asparaginase toxicity by inhibiting protein degradation. Overexpression of FBXW7, an E3 ubiquitin ligase that stimulates degradation of GSK3-phosphorylated proteins, rescued the asparaginase-sensitizing effect of NKD2 or LGR6 knockdown, further indicating that WNT activation cooperates with asparaginase treatment by affecting WNT-dependent protein stabilization. Combining a GSK3α-specific inhibitor with asparaginase in asparaginase-resistant ALL patient-derived xenograft models was highly efficacious, well tolerated, and significantly extended survival. Collectively, these observations support the development of GSK3 inhibitors as a combination therapy to be used with asparaginase for ALL and provide an example of using synthetic lethality to improve the therapeutic window of broad-acting cancer drugs.

Hinze L, Pfirrmann M, Karim S, Degar J, McGuckin C, Vinjamur D, et al. Synthetic lethality of Wnt pathway activation and asparaginase drug-resistant acute leukemias. Cancer Cell 2019;35:664–76.

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