Abstract A35: Overcoming Venetoclax Resistance in Acute Myeloid Leukemia (AML) via the Novel Imipridone ONC213 (2023)

Abstract Older adults make up most of the AML patient population and have an especially dismal prognosis due to limited therapeutic options. The Bcl-2 inhibitor, venetoclax (VEN), was approved for use in combination with low-dose cytarabine or a hypomethylating agent [azacitidine (AZA) or decitabine] in AML patients who are ≥75 years old or ineligible for intensive chemotherapy (IC). Due to superior survival data and tolerability, the combination of VEN and AZA has become a new standard of care for older patients and those unfit for IC. Though this was a promising therapeutic option for these patients, resistance to this therapy results in a 1-year overall survival rate of only 30-40% and the median overall survival following treatment failure is less than three months, highlighting the urgent need of new therapies to address this. Previous studies have found VEN resistance can be overcome by targeting mitochondria and Mcl-1. Our studies on ONC213, a novel imipridone, have found that it has potent antileukemic activity against both AML cell lines and primary patient samples. It reduces Mcl-1 and targets mitochondria of AML cells – and was thus a promising agent to overcome VEN resistance. When used in combination, ONC213 and VEN are highly synergistic in both AML cell lines and primary patient samples, including those intrinsically resistant to VEN. The combination also targets AML progenitor cells determined by colony formation assays and shows in vivo efficacy in a cell line derived xenograft mouse model (median survival of 57 days vs 37 days in control mice, p=0.002). To determine if ONC213 could overcome acquired resistance to VEN and AZA, we developed VEN and AZA double resistant ML-2 and MV4-11 AML cells (designated ML-2/VEN+AZA-R and MV4-11/VEN+AZA-R) by stepwise increasing concentrations of VEN and AZA at 1:3 fixed ratio over an extended period. ML-2/VEN+AZA-R and MV4-11/VEN+AZA-R AML cells demonstrate 437- and 1156-fold, respectively, increase in VEN+AZA (1:3 ratio) IC50 compared to parental cells (5,285.3 nM vs 12.1 nM and 6,704.3 nM vs 5.8 nM, respectively). ONC213 can resensitize resistant cells to VEN and the combination of ONC213 and VEN is highly synergistic in both ML-2/VEN+AZA-R and MV4-11/VEN+AZA-R cells as evident by a combination index (CI) value of &amp;lt; 0.05. ONC213 alone and in combination with VEN suppress oxidative phosphorylation (OXPHOS) and Mcl-1 in AML cells, including those with inherent resistance to VEN or with acquired resistance to VEN+AZA. Overexpression of Mcl-1 can partially rescue cells from combination therapy. These results suggest that ONC213 suppresses OXPHOS and Mcl-1 to overcome VEN resistance. Here we demonstrate that VEN resistance can be addressed through dual targeting of mitochondria and Mcl-1 using the novel imipridone, ONC213. ONC213 resensitizes VEN + AZA resistant cells to VEN and offers a new approach to combat VEN+AZA resistance in AML. Citation Format: Jenn L. Carter, Yongwei Su, Holly Edwards, Lisa Polin, Joshua E. Allen, Varun V. Prabhu, Jay Yang, Maik Huettermann, Yubin Ge. Overcoming Venetoclax Resistance in Acute Myeloid Leukemia (AML) via the Novel Imipridone ONC213 [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A35.