Combined targeting of ATR and replicative stress in TP53-mutated AML
Jeremy Baeten
PhDWashington University in St. Louis
Project Term: July 1, 2022 - June 30, 2024
This research will test a promising new drug combination in acute myeloid leukemia (AML) carrying TP53 gene mutations, which is resistant to chemotherapy and has a median survival of less than 5 months. Our preliminary data show that TP53-mutated AML is selectively sensitive to the combination of an ATR inhibitor and decitabine. We will confirm activity of this novel drug combination using mouse models of leukemia and human AML samples and explore mechanisms of responsiveness.
Acute myeloid leukemia (AML) carrying mutations of the TP53 gene represents a very-high risk subgroup of AML. TP53-mutated AML is resistant to standard induction chemotherapy and has a dismal prognosis, with a median survival of less than 5 months. We previously reported that the majority of patients with TP53-mutated AML respond to decitabine, a hypomethylating agent (drug that decreases methylation marks on the DNA). However, these responses were not durable. Thus, there remains a pressing need for better therapies for patients with TP53-mutated AML. In our preliminary studies to identify molecular determinants of response to decitabine, we discovered that this drug impairs DNA replication, the process by which DNA is copied when cells grow and divide. This impaired DNA replication activates the ATR gene, which halts cell division and allows the cells time to complete DNA replication. Treatment with an ATR inhibitor (AZD6738) overcomes this decitabine-induced block in cell division, inducing cell death. Strikingly, TP53-mutated AML is much more sensitive to the combination of decitabine and ATR inhibition. Indeed, this drug combination induces potent synergistic killing in TP53-mutated AML. In this proposal, we will rigorously assess the therapeutic activity of decitabine and AZD6738 in TP53-mutated AML using animal models and patient-derived AML samples. We also will explore molecular mechanisms by which these drugs synergistically kill TP53-mutated AML, looking closely at how they progress through cell division, the speed and accuracy of their DNA replication, and whether they accumulate damage to their DNA after treatment. Ultimately, this research may support a clinical trial of an ATR inhibitor combined with decitabine for TP53-mutated AML. Understanding the mechanisms of this combination could also help inform treatment of other cancers carrying TP53 mutations. Our proposal seeks to add a new treatment option for a disease with far too few and impact the lives of the thousands of TP53-mutated AML patients diagnosed each year.