# Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $450,484

## Abstract

ABSTRACT
Asparaginase, an antileukemic enzyme that depletes the nonessential amino acid asparagine, is a core
component of front-line therapy for acute lymphoblastic leukemias. However, the development of resistance to
asparaginase-based therapy is a common problem with a poor prognosis, and the biology underlying
asparaginase response and resistance is not well understood. Using a genome-wide genetic screen, we recently
found that Wnt pathway activation profoundly sensitizes drug-resistant leukemias to asparaginase. This effect
occurs in distinct treatment-resistant subtypes of acute leukemia, including T-ALL, hypodiploid B-ALL, and acute
myeloid leukemia, but not in normal hematopoietic progenitors. Asparaginase sensitization is independent of
the canonical β-catenin branch of Wnt signaling. Instead, this effect is mediated by Wnt-dependent stabilization
of proteins (Wnt/STOP), an understudied branch of Wnt signaling that inhibits GSK3-dependent protein
ubiquitination and proteasomal degradation. Inhibiting the alpha isoform of GSK3 is sufficient to phenocopy this
effect. In vivo, the combination of GSK3α-selective inhibition and asparaginase has profound therapeutic activity
against patient-derived xenografts that are completely resistant to monotherapy with either agent. Thus,
asparaginase-resistant leukemias survive treatment with this enzyme by relying on protein degradation, a
catabolic source of amino acids, to replenish the pool of intracellular asparagine. This adaptive response is
blocked by Wnt pathway activation, or by selective inhibition of GSK3α. However, the molecular determinants
of response and resistance to the combination of GSK3α inhibition and asparaginase are unknown. These
knowledge gaps are major obstacles to the rational application of this potent therapeutic combination for maximal
clinical benefit, which will be addressed by investigating the following Specific Aims: 1) Define the molecular
basis for the therapeutic index of GSK3α inhibition and asparaginase, and 2) Investigate why asparaginase
resistance is solely dependent on GSK3α, when its closely related paralog GSK3β is redundant for regulation of
canonical Wnt/β-catenin signaling. Successful completion of this proposal is expected to reveal major insights
into the cellular response to amino acid starvation and its interaction with Wnt signaling. These processes are
fundamental to metazoan biology, yet their molecular regulation and therapeutic exploitation remain poorly
understood. We are uniquely poised to translate these advances into highly innovative and effective therapeutic
strategies to maximize the therapeutic index of asparaginase in cancer therapy.

## Key facts

- **NIH application ID:** 10172856
- **Project number:** 5R01CA193651-07
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Alejandro Gutierrez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,484
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172856

## Citation

> US National Institutes of Health, RePORTER application 10172856, Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias (5R01CA193651-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172856. Licensed CC0.

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