Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis

Paiva, Cody; Godbersen, J. Claire; Rowland, Taylor; Danilova, Olga V.; Danes, Christopher G.; Berger, Allison; Danilov, Alexey V.

doi:10.18632/oncotarget.15050

Cited by 13 publications

(10 citation statements)

References 57 publications

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“…While FLIP downregulation in response to MLN4924 has been reported, this effect was observed using higher concentrations of MLN4924 over longer periods than used in our study 48,49 ; and indeed we also observed a downregulation of FLIP(L) after 24hrs of treatment (Supplementary Figure 7B).…”

Section: Discussionsupporting

confidence: 69%

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Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

Longley

Roberts

Holohan

et al. 2019

Preprint

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Depending on its expression levels, the long splice form of the pseudo-caspase FLIP (FLIP(L)) can act as an inhibitor (high expression) or activator (low expression) of apoptosis induction by the TRAIL-R2 death-inducing signalling complex (DISC); its expression levels are therefore tightly regulated. Here, we demonstrate that the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCF Skp2 ) regulates the stability of FLIP(L) (but not the short splice form FLIP(S)), and, unusually, this is mediated by direct binding of FLIP(L) to Cullin-1 rather than via Skp2. By fine mapping the interaction of FLIP(L) with Cullin-1 to the large subunit of its pseudo-caspase domain, we found that the interaction is significantly stronger with FLIP(L)'s DISC-processed p43-form.Importantly, this interaction disrupts the ability of p43-FLIP to interact with FADD, caspase-8 and another DISC component, TRAF2. Moreover, we find that SCF Skp2 associates with TRAIL-R2 constitutively and does so independently of FLIP(L) and other canonical DISC components. Inhibition of Cullin-1 expression (using siRNA) or activity (using a NEDDylation inhibitor, MLN4924) enhanced FLIP(L) and TRAF2 levels at the TRAIL-R2 DISC and enhanced caspase-8 processing. This suggests that processing of FLIP(L) to p43-FLIP at the TRAIL-R2 DISC enhances its interaction with co-localised SCF Skp2 , leading to disruption of p43-FLIP's association with the DISC thereby altering caspase-8 processing. These findings provide important new insights into how FLIP(L) expression and TRAIL-R2 signaling is controlled. Regulation of FLIP(L) and TRAIL signalling by SCF Skp2JZ Roberts et al. 3 IntroductionProgrammed cell death (apoptosis) plays a key role in maintaining normal tissue homeostasis and preventing disease 1 . Apoptosis is orchestrated by a family of cysteine proteases, the caspases 2 . The multi-protein complexes formed following activation of the CD95 (Fas) and TRAIL-R1/R2 (DR4/DR5) death receptors by their ligands (FasL and TRAIL) expressed by immune effector cells and by 2 nd generation therapeutic agonists (ABBV621 and MEDI3039) is called the death-inducing signalling complex (DISC), consisting of the receptors, the adaptor molecule FADD, procaspase-8 and FLIP 3 .Recruitment into these complexes exposes FADD's N-terminal death effector domain (DED), which recruits procaspase-8 by interacting with its N-terminal tandem DEDs 4 . Procaspase-8 homodimerization results in conformational changes in its catalytic domains that lead to its activation 5 . Two main splice forms of FLIP have been identified in humans: a long form (FLIP(L)) and a short form (FLIP(S)), both of which contain tandem DEDs and can be recruited to the DISC and related complexes (such as TNFR1 Complex II and the ripoptosome) where they form heterodimers with procaspase-8 4 . The relative amounts of FLIP(S) and FLIP(L) recruited to these complexes is a key determinant of cell fate (survival, apoptosis or necroptosis) and whether FLIP(L) acts as an inhibitor or activator o...

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Section: Discussionsupporting

confidence: 69%

“…Therefore, MLN4924 has a biphasic effect on FLIP(L), with early upregulation followed by downregulation potentially due to suppression of NFB, a known regulator of FLIP expression 50 and a known target of MLN4924 49,51,52 . In this study, we focussed on the more direct early effects of MLN4924 on FLIP(L) and the TRAIL-R2 DISC.…”

Section: Discussionmentioning

confidence: 99%

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

Longley

Roberts

Holohan

et al. 2019

Preprint

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“…When combined with panobinostat and vorinostat, the latency reversal activity of Debio 1143 was amplified (Fig 3B). Debio 1143 was as efficient or even more efficient than other IAPa tested such as LCL161 [53], TL32711 (Birinapant) [54] and GDC-052 [55] (Fig 3C). In contrast to Debio 1143, several LRAs were toxic to cells (Fig 3D).…”

Section: Resultsmentioning

confidence: 99%

The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate

et al. 2019

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Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-κB-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).

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“…Pevonedistat induces a pro‐apoptotic milieu and downregulates NF‐κB activity, which makes it an attractive partner for drug combinations. Prior studies have demonstrated that in CLL and DLBCL, pevonedistat restored sensitivity to death receptor‐mediated apoptosis through the mitochondrial pathway [24]. In CLL, it also induced DNA damage and checkpoint activation by deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27 [25].…”

Section: Discussionmentioning

confidence: 99%

Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma

Torka

Mavis

Kothari

et al. 2020

eJHaem

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We studied the biological activity of pevonedistat, a first‐in‐class NEDD8‐activating enzyme (NAE) inhibitor, in combination with various cytotoxic chemotherapy agents and small molecule inhibitors in lymphoma preclinical models. Pevonedistat induced cell death in activated B‐cell (ABC) diffuse large B‐cell lymphoma (DLBCL) cell lines and to a lesser degree in germinal center B‐cell (GCB) DLBCL cell lines. In pevonedistat sensitive cells, we observed inhibition of NF‐κB activity by p65 co‐localization studies, decreased expression of BCL‐2/Bcl‐XL, and upregulation of BAK levels. Pevonedistat enhanced the activity of cytarabine, cisplatin, doxorubicin, and etoposide in ABC‐, but not in the GCB‐DLBCL cell lines. It also exhibited synergy with ibrutinib, selinexor, venetoclax, and A‐1331852 (a novel BCL‐XL inhibitor). In vivo, the combination of pevonedistat and ibrutinib or pevonedistat and cytarabine prolonged survival in SCID mice xenograft models when compared with monotherapy controls. Our data suggest that targeting the neddylation pathway in DLBCL is a viable therapeutic strategy and support further clinical studies of pevonedistat as a single agent or in combination with chemotherapy or novel targeted agents.

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Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis

Cited by 13 publications

References 57 publications

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate

Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma

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Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis

Cited by 13 publications

References 57 publications

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCFSkp2Ubiquitin Ligase Complex

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCFSkp2Ubiquitin Ligase Complex

The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate

Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma

Contact Info

Product

Resources

About

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex