Abstract 1877: Selective inhibitor of nuclear export (SINE) compound, eltanexor (KPT-8602), synergizes with venetoclax (ABT-199) to eliminate leukemia cells and extend survival in an in vivo model of acute myeloid leukemia

Abstract

Abstract SINE compounds (KPT-330/selinexor and KPT-8602/eltanexor) are a novel class of small molecules with therapeutic potential across a broad range of cancers. SINE compounds target exportin 1 (XPO1), which is an essential nucleo-cytoplasmic transport protein, responsible for the nuclear export of >200 cargo proteins including many tumor-suppressor proteins (TSPs) and oncogenes, such as p53, IκB, BCL-2, eIF4E and MYC. XPO1 is overexpressed in numerous solid and hematologic malignancies, often correlating with poor prognosis. An important family of oncoproteins regulated by SINE compounds are the pro-survival BCL-2 family proteins, BCL-2 and MCL-1, as both are transported from the nucleus by forming a complex with the XPO1 cargo protein, elF4E. BCL-2 and MCL-1 are dysregulated and linked to maintenance and survival in numerous cancers. Early studies with venetoclax (VEN/ABT-199), a potent, selective inhibitor of BCL-2, have revealed response rates from 50-80% across a variety of hematologic malignancies. However, resistance often arises via upregulation of other BCL-2 family antiapoptotic proteins, most commonly MCL-1. Thus, we hypothesized that co-treatment of VEN and SINE compounds would show enhanced cell killing in AML due to the ability of SINE to further block the prosurvival signals of both BCL-2 and MCL-1. Co-treatment with eltanexor and VEN demonstrated synergistic loss of viability in multiple hematologic malignancy cell lines, particularly MV-4-11 cells. Further in vitro analysis showed this enhanced cell death was due to an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays. We used in vivo studies to test the effect of this combination in a systemic AML xenograft model. For this, MV-4-11 cells were transplanted into NSGS mice and allowed to engraft before treating the mice with vehicle, eltanexor, VEN, or a combination of the two compounds. When the vehicle mice became moribund at 4 weeks after transplant, all treatment groups were sacrificed to compare leukemic burden in the hematopoietic tissues. Flow cytometric analysis revealed a drastic elimination of leukemic cells in the bone marrow, spleen, and peripheral blood of the combination-treated mice compared to vehicle and single-treatment groups. Immunohistochemical analysis of the spleen and bone marrow confirmed this finding, and also revealed the reduction in leukemic cells was due, in part, to an induction of apoptosis (an increase in cleaved caspase 3 and decrease in survivin) in splenic tissue sections, in agreement with the in vitro results. Finally, the dramatic clearance of leukemia cells in the mouse caused by eltanexor and VEN treatment led to prolonged survival. Our results demonstrate the potential of this combination regimen in the treatment of AML. Citation Format: Melissa A. Fischer, Pia M. Arrate, Hua Chang, Agnieszka E. Gorska, Londa S. Fuller, Haley E. Ramsey, Trinayan Kashyap, Christian Argueta, William Senapedis, Erkan Baloglu, Yosef Landesman, Sharon Shacham, Michael R. Savona. Selective inhibitor of nuclear export (SINE) compound, eltanexor (KPT-8602), synergizes with venetoclax (ABT-199) to eliminate leukemia cells and extend survival in an in vivo model of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1877.