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Updated: Jul 16, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeting WEE1 kinase as a p53-independent therapeutic strategy in high-risk and relapsed acute lymphoblastic
Hayden L Bell1, Helen J Blair1, Mankaran Singh1
1Wolfson Childhood Cancer Research Centre, Translation and Clinical Research Institute, Newcastle University Centre for Cancer,, Newcastle Upon Tyne, UK.
Background:
Outcomes for patients with relapsed acute lymphoblastic leukemia (ALL) are poor and there is a need for novel therapies to improve outcomes. Targeted inhibition of WEE1 with small-molecule inhibitor adavosertib (AZD1775) has emerged as a therapeutic strategy to sensitize cancer cells to DNA-damaging chemotherapeutics, particularly in the context of TP53-mutated tumors. However, WEE1 inhibition as a potential therapeutic strategy for patients with high-risk and relapsed ALL, including those with TP53 mutations, has not been definitively evaluated.
Methods:
Anti-leukemic effects of adavosertib were investigated using a relapsed TP53 isogenic cell model system, primary patient, and patient-derived ALL samples (n = 27) in an ex vivo co-culture model system with bone marrow-derived mesenchymal stem cells. Combination effects with drugs currently used for relapsed ALL were quantified by Excess over Bliss analyses. Investigations for alterations of cell cycle and apoptosis as well as related proteins were examined by flow cytometry and Western blot, respectively.
Results:
Our study demonstrates the potent anti-leukemic activity of the clinically advanced WEE1 inhibitor adavosertib in a large majority (n = 18/27) of high-risk and relapsed ALL specimens at lower than clinically attainable concentrations, independent of TP53 mutation status. We show that treatment with adavosertib results in S-phase disruption even in the absence of DNA-damaging agents and that premature mitotic entry is not a prerequisite for its anti-leukemic effects. We further demonstrate that WEE1 inhibition additively and synergistically enhances the anti-leukemic effects of multiple conventional chemotherapeutics used in the relapsed ALL treatment setting. Particularly, we demonstrate the highly synergistic and cytotoxic combination of adavosertib with the nucleoside analog cytarabine and provide mechanistic insights into the combinational activity, showing preferential engagement of apoptotic cell death over cell cycle arrest. Our findings strongly support in vivo interrogation of adavosertib with cytarabine in xenograft models of relapsed and high-risk ALL.
Conclusions:
Together, our data emphasize the functional importance of WEE1 in relapsed ALL cells and show WEE1 as a promising p53-independent therapeutic target for the improved treatment of high-risk and relapsed ALL.
Insights
Adavosertib, a WEE1 inhibitor, shows potent anti-leukemic activity in relapsed acute lymphoblastic leukemia (ALL) regardless of TP53 mutation status. It synergizes with cytarabine, offering a promising therapeutic strategy for high-risk ALL.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Outcomes for relapsed acute lymphoblastic leukemia (ALL) remain poor, necessitating novel therapeutic approaches.
- Targeted WEE1 inhibition with adavosertib is a strategy to sensitize cancer cells to DNA-damaging agents, particularly in TP53-mutated tumors.
- The efficacy of WEE1 inhibition in high-risk and relapsed ALL, including TP53-mutated cases, requires further evaluation.
Purpose of the Study:
- To investigate the anti-leukemic effects of adavosertib in relapsed acute lymphoblastic leukemia (ALL).
- To evaluate adavosertib's efficacy independently and in combination with conventional chemotherapeutics.
- To explore the mechanistic basis of adavosertib's activity and its potential as a therapeutic target.
Main Methods:
- Utilized a relapsed TP53 isogenic cell model and primary patient-derived ALL samples (n=27) in an ex vivo co-culture system.
- Quantified combination effects with standard relapsed ALL drugs using Excess over Bliss analyses.
- Assessed cell cycle alterations and apoptosis via flow cytometry and Western blot analysis.
Main Results:
- Adavosertib demonstrated potent anti-leukemic activity in a majority of high-risk and relapsed ALL specimens (18/27) at sub-clinical concentrations, irrespective of TP53 mutation status.
- Adavosertib induced S-phase disruption and enhanced the efficacy of conventional chemotherapeutics, particularly cytarabine, through synergistic cytotoxicity.
- Combinational therapy with adavosertib and cytarabine preferentially induced apoptotic cell death over cell cycle arrest.
Conclusions:
- WEE1 inhibition is functionally important in relapsed ALL cells.
- WEE1 represents a promising p53-independent therapeutic target for improving outcomes in high-risk and relapsed ALL.
- Further in vivo studies of adavosertib in combination with cytarabine are warranted.
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