Triple combination of BET plus PI3K and NF-κB inhibitors exhibit synergistic activity in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell lymphoproliferative malignancy, caused by human T-cell leukemia virus type 1 (HTLV-1). ATL is an orphan disease with no curative drug treatment regimens, urgently needing new combination therapy. HTLV-1-infected cells rely on viral proteins, Tax and HBZ (HTLV-1-b-ZIP factor), to activate the transcription of various host genes that are critical for promoting leukemic transformation. Inhibition of bromodomain and extra-terminal motif (BET) protein was previously shown to collapse the transcriptional network directed by BATF3 super-enhancer and thereby induced ATL cell apoptosis. In the current work, by using xenograft, ex vivo, and in vitro models, we demonstrated that I-BET762 (BETi) synergized with copanlisib (PI3Ki) and bardoxolone methyl (NF-κBi) to dramatically decrease the growth of ATL cells. Mechanistically, the triple combination exhibited synergistic activity by down-regulating the expression of c-MYC while up-regulating the level of the glucocorticoid-induced leucine zipper (GILZ). The triple combination also enhanced apoptosis induction by elevating the expression of active caspase-3 and cleaved PARP. Importantly, the triple combination prolonged the survival of ATL-bearing xenograft mice and inhibited the proliferation of ATL cells from PBMCs of both acute and smoldering/chronic ATL patients. Therefore, our data provide the rationale for a clinical trial exploring the multi-agent combination of BET, PI3K/AKT, and NF-κB inhibitors for ATL patients, and expands the potential treatments for this recalcitrant malignancy.

Human T-Cell Leukemia Virus Type 1 Oncogenesis between Active Expression and Latency: A Possible Source for the Development of Therapeutic Targets

“…The combination of ruxolitinib, an inhibitor of the JAK/STAT pathway constitutively activated in HTLV-1-transformed T cells [95], and the Bcl-2/Bcl-xL inhibitor navitoclax showed antitumor efficacy in an additive/synergistic manner on IL-2-dependent ATL cell lines and ex vivo on lymphocytes from ATL patients [96]. Recently, a triple combination of NF-κB and PI3K inhibitors with an inhibitor of the oncogenic driver Bromine and Extra-Terminal domain (BET) motif family, involved in the down-regulation of MYC transcription, was used synergistically to achieve an antiproliferative effect in ATL cells in vitro and ex vivo [97]. To evaluate the response of ATL patients to treatment in vivo, it may be critical to determine the efficacy of therapy on viral replication in addition to its effects on cell survival.…”

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

“…This phenomenon is especially evident in extended enhancer sequences that are rich in transcription factor binding sites, and are termed stretch enhancers, or superenhancers [ 51 , 52 ]. Superenhancer changes are associated with cancer progression; in leukemia, specific feedforward loops are proposed to drive disease progression by switching on expression of NFκB downstream genes that include but are not limited to Myc [ 53 , 54 , 55 ]. After stimulation of embryonic kidney cells with TNFα, OGG1 and NFκB were found to bind to DNA recognition sites of organic cation transporter (OCT2), sex-determining region Y box transcription factor (SOX), and other families of regulators of cellular development by chromatin immunoprecipitation [ 56 ].…”

HTLV‐1 persistent infection and ATLL oncogenesis

“…Standard treatments of ATLL mainly include intensive chemotherapy and a zidovudine/interferon α (AZT/IFN‐α) combination therapy; however, these treatments are not satisfactory, particularly in aggressive types of ATLL, and targeted therapy has been explored with high hope. Many cellular genes that are dysregulated by HTLV‐1 have been reported and might serve as possible ATLL targets (Figure 4), including bromodomain‐and‐extra‐terminal‐domain (BET) proteins 70,71 and oxysterol‐binding protein‐related protein 4L (ORP4L) 72 identified very recently, yet solid translational work is required to evaluate their druggability and effectiveness for targeted ATLL therapy. In addition, epigenetic inhibitors are an alternative option for ATLL treatment, and targeting EZH2 and HDAC has yielded promising results in preclinical and phase I trials 73 …”