Abstract 4316: MCL-1 inhibition ameliorates the expansion of human leukemia in a dose dependent fashion

Abstract

Abstract Myeloid cell leukemia-1 (MCL-1) is a prosurvival BCL-2 family member protein commonly overexpressed in cancer, including hematologic malignancies. The successful use of BH3 mimetics against other anti-apoptotic proteins has validated the potential of this line of therapy in hematologic malignancies. However, targeting BCL-2 family members, like MCL-1, with a small molecule inhibitor is challenging because these inhibitors mediate their effects through protein-protein interactions. Recently, we discovered potent (sub nM), selective small molecule MCL-1 inhibitors that exhibit cell-based activity and slow the growth of tumors in multiple mouse models. To determine tumor cell dependence on specific BCL2-family members, we employed BH3 profiling on a panel of myeloid tumor cells to reveal mitochondrial outer membrane permeablization (MOMP) in a cytochrome C release assay. Additionally, we determined growth inhibition of these cell lines in the presence of the potent MCL-1 inhibitor. These assays indicated MV-411 cells were dependent on MCL-1 and sensitive to MCL-1 inhibition with a GI50 <100nM. After cell line profiling, we began in vivo studies with the MCL-1 inhibitor in a systemic AML xenograft model. NSGS mice were sublethally irradiated and administered MV-411 cells intravenously. Engrafted mice received the MCL-1 inhibitor in 3 different doses (vehicle vs 10, 25 and 75mg/kg) daily via intraperitoneal injection. During treatment, the kinetics of MV-411 expansion was monitored via flow cytometry for the detection of human AML in the blood. At approximately 4 weeks after transplant, the vehicle mice became moribund, and all experimental groups were sacrificed for analysis of chimerism. Significant decreases in leukemic expansion were evident in the bone marrow (25 and 75mg/kg vs vehicle, P= .01, P <.001) and spleen (vehicle vs. 75mg/kg, P<.001) of treated mice in a dose-dependent fashion. MCL-1 blockade also eliminated splenomegaly in MCL-1 inhibitor treated mice. Successful use of the BCL-2 inhibitor, venetoclax, as a single agent and in combination with DNA methyltransferase inhibitors or low dose ara-C has proven the powerful role BH3 mimetics may play in AML therapy. However, mediation of resistance via alternative BCL-2 family antiapoptotic proteins remains a concern, and development of suitable inhibitors of MCL-1 and BCL-XL is important. These data show that we have developed a potent MCL-1 inhibitor, with in vivo efficacy in an AML mouse model. Further studies can determine the potential use of this drug to overcome resistance in the clinic. In addition, we will employ dynamic BH3 profiling of patient samples to determine the combination and sequencing of therapeutically applied BH3 mimetics. Citation Format: Haley E. Ramsey, Melissa A. Fischer, Taekyu Lee, Agnieszka E. Gorska, Pia Arrate, John Sensintaffer, Leah Hogdal, Edward Olejniczak, Stephen Fesik, Michael R. Savona. MCL-1 inhibition ameliorates the expansion of human leukemia in a dose dependent fashion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4316. doi:10.1158/1538-7445.AM2017-4316