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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML
Jeremy T Baeten1, Sumedha Agashe1, Imene Tabet1
1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Abstract:
TP53 mutations are found in 10% to 15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents (HMAs), such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to HMAs in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ataxia telangiectasia mutated-Rad3-related (ATR) pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNA methyltransferase 1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and an ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these findings show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATRi and decitabine showing promise as a new therapeutic approach for TP53-MN.
Insights
TP53 mutations in myeloid neoplasms worsen prognosis. Combining decitabine with ATR inhibitors offers a novel therapeutic strategy by exploiting decitabine-induced replication stress in TP53-mutated acute myeloid leukemia.
Area of Science:
- Hematology
- Cancer Biology
- Molecular Oncology
Background:
- TP53 mutations occur in 10-15% of myeloid neoplasms, correlating with poor outcomes.
- Hypomethylating agents like decitabine show activity but rarely achieve complete remission in TP53-mutated myeloid neoplasms (TP53-MN).
- Understanding molecular responses to hypomethylating agents in TP53-MN is crucial for improving treatment.
Purpose of the Study:
- To investigate the molecular mechanisms underlying decitabine response in TP53-mutated myeloid neoplasms.
- To identify potential therapeutic vulnerabilities in TP53-mutated acute myeloid leukemia (TP53-AML).
- To evaluate the efficacy of combining decitabine with ATR inhibition as a novel treatment strategy.
Main Methods:
- Assessed decitabine's effects on DNA replication, DNA breaks, and ATR pathway activation in TP53-AML cells.
- Investigated the impact of combining decitabine with ATR inhibitors (ATRi) on TP53-AML cell viability.
- Evaluated the combination therapy in in vivo mouse models of TP53-AML.
Main Results:
- Decitabine induces replicative stress, DNA breaks, and ATR pathway activation, which is poorly resolved in TP53-AML cells.
- The combination of decitabine and ATRi leads to synthetic lethality selectively in TP53-AML, partly via mitotic catastrophe.
- This synergistic effect was not observed with azacitidine or a DNMT1 inhibitor.
- Combined decitabine and ATRi treatment reduced leukemia burden and improved survival in preclinical models.
Conclusions:
- TP53 loss creates a specific vulnerability to decitabine-induced replication stress in myeloid neoplasms.
- Combining decitabine with ATR inhibition presents a promising new therapeutic avenue for TP53-mutated myeloid neoplasms.
- Targeting replication stress resolution pathways may overcome resistance to hypomethylating agents in TP53-mutated AML.
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