Abstract

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.

Highlights

  • Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous clonal disease characterized by remains the most promising modality to effect cure.allo-HCT can be offered only to a minority of younger, fit patients, whereas AML primarily affects individuals older than 60 who are not suitable candidates[3]

  • The in vitro antiproliferative activity of APG-115 was first evaluated in a panel of five distinct AML cultures, including three TP53 wild-types (TP53wt; MOLM-13, MV-4-11, OCI-AML-3), a TP53 null (TP53null; HL-60), and a TP53 mutant (TP53mut; SKM-1) cell lines (Fig. 1A)

  • Mean (SD) values of IC50 for APG-115 were 26.8 (4.9) nM in MOLM-13, 165.9 (42.4) nM in MV4-11, and 315.6 (97) nM in OCI-AML-3 cells (Supplementary Table 1). Compared to these TP53wt cells, HL-60 and SKM-1 cells with defected TP53 were resistant to APG-115 treatment, with mean (SD) IC50 values of 2558.3 (581.5) nM in HL-60 cells and 8,947.3 (569.6) nM in SKM-1 cells (Supplementary Table 1)

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Summary

Introduction

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous clonal disease characterized by remains the most promising modality to effect cure.allo-HCT can be offered only to a minority of younger, fit patients, whereas AML primarily affects individuals older than 60 who are not suitable candidates[3]. Patients who have AML and are ineligible for allo-HCT and/or harbor high-risk karyotypes typically have poor outcomes, with an estimated median overall survival of only 1 year[4]. The regimen of choice for induction in many patients with newly diagnosed AML is the DNA-damaging agent cytarabine (Ara-C), administered daily for 7 days, followed by daunorubicin for 3 days[10,11]. This so-called 7 + 3 regimen has been associated with high drug resistance and a low 5-year OS rate[12,13]. There is an urgent need to identify novel agents that enhance clinical outcomes in AML

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