BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor

Abstract

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel and pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. .

Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia

“…Treatment with JQ1 led to dramatic inhibition of cell proliferation and proved efficacious in xenografted mice with disseminated CLL tumors. Recently, a structurally dissimilar BET inhibitor PLX51107 was reported to have similar effects in pre-clinical models of CLL, with transcriptional disruption of B cell receptor signaling genes in proximity to BRD4-bound super enhancers including PAX5 (Ozer et al, 2018). Thus, this class of pharmacologic agent may prove useful for CLL therapy, perhaps in combination with other agents targeting B cell signaling.…”

Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma

“…The structure of PLX51107 is reported previously (Ozer et al, 2018 PLX51107 and PLX72853 were provided by Plexxikon, Inc.…”

“…Indeed, we have previously reported JQ1 to be highly effective in inhibiting the growth of GNAQ/GNA11 mutant UM cells associated with downregulation of DNA damage response genes, Bcl-xL and Rad51 (Ambrosini et al, 2015). A next-generation BET inhibitor, PLX51107 (Ozer et al, 2018;Plexxikon, Inc., Berkeley, CA), that has a half-life of 2.8 h and a broader therapeutic index, is currently being tested in clinical trials for patients with advanced malignancies including UM (NCT02683395). A next-generation BET inhibitor, PLX51107 (Ozer et al, 2018;Plexxikon, Inc., Berkeley, CA), that has a half-life of 2.8 h and a broader therapeutic index, is currently being tested in clinical trials for patients with advanced malignancies including UM (NCT02683395).…”

“…However, JQ1 is not tested clinically due to its short half-life (t 1/2 : 0.9-1.4 h) (Filippakopoulos et al, 2010) and resistance to other BET inhibitors has been reported despite pre-clinical success of BET inhibitors (Fong et al, 2015;Rathert et al, 2015;Kurimchak et al, 2016). A next-generation BET inhibitor, PLX51107 (Ozer et al, 2018;Plexxikon, Inc., Berkeley, CA), that has a half-life of 2.8 h and a broader therapeutic index, is currently being tested in clinical trials for patients with advanced malignancies including UM (NCT02683395). In UM, mechanisms of resistance to BET inhibitors are not known.…”

PLX3397 inhibits the accumulation of intra‐tumoral macrophages and improves bromodomain and extra‐terminal inhibitor efficacy in melanoma

“…PLX51107 differentially altered the growth of mouse Braf V600E melanoma tumors, effects that were associated with the influx of TAM. PLX3397, a colony-stimulating factor-1 re- (Ao et al, 2017;Ozer et al, 2018).…”