The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains

Abstract

Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

The anti‐mitotic agents PTC‐028 and PTC596 display potent activity in pre‐clinical models of multiple myeloma but challenge the role of BMI‐1 as an essential tumour gene

“…Synergism of concurrent BMI-1 and EZH2 blockade was previously described in MM and other entities. 13,35 However, whether this synergism observed in the present study is driven via BMI-1 degradation needs to be clarified in future studies. Moreover, in U266 concurrent EZH2 blockade appeared less effective in coculture, which might be a consequence of modulation of EZH2 activity by the presence of stromal cells.…”

“…We and others recently confirmed BMI-1 overexpression as a hallmark of MM and its putative role as a drug target using the small molecule inhibitor PTC-209. 13,14 Based on these observations, in the present study, we explored the anti-myeloma efficacy of the first-in-class BMI-1 modulators PTC-028 and PTC596. BMI-1 modulators have been described to target BMI-1 in an indirect manner via inhibition of the anaphase promoting complex (APC/C) CDC20 leading to persistent cyclin-dependent kinase (CDK)1/2 activity and BMI-1 hyper-phosphorylation, as well as reduced PRC1 activity.…”

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…BMI1 inhibition, using a small molecule inhibitor, PTC209, induced apoptosis in MM cell lines and primary MM cells in vitro . PTC209 exhibited synergistic and additive anti‐MM effects when combined with pomalidomide and carfilzomib, as well as EZH2 and BET‐targeting epigenetic inhibitors . Further, BMI1 shRNA was effective in reducing tumor growth of MM xenografts in mice .…”

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

“…Further preclinical work is required to validate the efficacy of DOT1L inhibition in MLLT10r AML and T-ALL, but DOT1L inhibition is currently the most advanced and promising therapeutic target for MLLT10r acute leukemia.7 | BMI1 INHIBITORSPICALM-MLLT10 AML is dependent on expression of BMI1, and murine and human models of PICALM-MLLT10-driven leukemias are sensitive to BMI1 inhibition 31,37,73. BMI1 is a polycomb group protein, responsible for the epigenetic repression of developmentally important genes, including CDKN2A locus genes p16 INK4A and p14 ARF , critical in the regulation of cell cycle progression and self-renewal of stem cells 37,84. Both genetic and pharmacological inhibition of BMI1impedes PICALM-MLLT10-driven myeloid transformation, and inhibits proliferation of human PICALM-MLLT10 AML cells in vitro and in murine xenotransplantation models.…”