Abstract A020: 5-Azacytidine primes AML cells for venetoclax-induced apoptosis by upregulating NOXA and PUMA protein expression

Abstract

Abstract Acute myeloid leukemia (AML) is a clonal hematologic malignancy characterized by complex heterogeneity and epigenetic features with an incidence of 20,830 new cases in 2015. Older patients, age ≥65 years, define a hard-to-treat population with a median overall survival (OS) of 2-8 months whose treatment options include induction chemotherapy, low-dose-Ara-C, best supportive care, and hypothemylating agents (HMAs). The HMA 5-Azacytidine (5-Aza) is an epigenetic targeting therapy that provides a median OS of 10.4 months in elderly AML patients (≥65 years of age; Dombret et al., 2015; Tamamyan et al., 2017). This antitumorigenic activity can be at least in part attributed to the induction of apoptosis since 5-Aza’s preclinical activity can be limited by members of the antiapoptotic BCL-2 protein family (Bogenberger et al., 2014). Venetoclax (ABT-199) is a highly selective, orally bioavailable BCL-2 inhibitor that is efficacious in numerous preclinical models of hematologic malignancies. A phase II clinical trial in heavily pretreated relapsed and refractory (R/R) AML patients has demonstrated venetoclax is active as a monotherapy (overall response rate (ORR) of 19%; Konopleva et al., 2016), providing the foundation for combinational studies with other antitumorigenic agents in AML. Early phase Ib clinical data in elderly AML patients (≥ 65 year of age) indicate that combining venetoclax with 5-Aza results in an ORR of 60-68% (Pratz et al., 2017). However, the underlying mechanism for the combinational activity observed between venetoclax and 5-Aza is unknown. Herein we report that 5-Aza upregulates the expression of the BH3-only proteins NOXA and PUMA in human AML cell lines. This is associated with an increase in the amount of NOXA and PUMA in complex with antiapoptotic BCL-2 proteins, serving to “prime” AML cells for induction of apoptosis by venetoclax treatment, and rationalizing the significant synergistic cell death observed when a panel of AML cell lines was treated with venetoclax and 5-Aza in vitro. Further, the venetoclax/5-Aza combination provided added benefit over either agent alone in two xenograft models of AML. Collectively these data provide a preclinical basis for an ongoing randomized phase III clinical trial evaluating venetoclax activity in combination with 5-Aza in treatment-naïve AML patients ineligible for standard induction therapy (M15-656, NCT02993523). Citation Format: Sha Jin, Julie Purkal, Relja Popovic, Yu Xiao, Larry Solomon, Erwin Boghaert, Joel Leverson, Darren C. Phillips. 5-Azacytidine primes AML cells for venetoclax-induced apoptosis by upregulating NOXA and PUMA protein expression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A020.