Abstract
Pevonedistat (MLN4924), a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit (NAE1), has demonstrated significant therapeutic potential in several malignancies. Although multiple mechanisms-of-action have been identified, how MLN4924 induces cell death and its potential as a combinatorial agent with standard-of-care (SoC) chemotherapy in colorectal cancer (CRC) remains largely undefined. In an effort to understand MLN4924-induced cell death in CRC, we identified p53 as an important mediator of the apoptotic response to MLN4924. We also identified roles for the extrinsic (TRAIL-R2/caspase-8) and intrinsic (BAX/BAK) apoptotic pathways in mediating the apoptotic effects of MLN4924 in CRC cells, as well as a role for BID, which modulates a cross-talk between these pathways. Depletion of the anti-apoptotic protein FLIP, which we identify as a novel mediator of resistance to MLN4924, enhanced apoptosis in a p53-, TRAIL-R2/DR5-, and caspase-8-dependent manner. Notably, TRAIL-R2 was involved in potentiating the apoptotic response to MLN4924 in the absence of FLIP, in a ligand-independent manner. Moreoever, when paired with SoC chemotherapies, MLN4924 demonstrated synergy with the irinotecan metabolite SN38. The cell death induced by MLN4924/SN38 combination was dependent on activation of mitochondria through BAX/BAK, but in a p53-independent manner, an important observation given the high frequency of TP53 mutation(s) in advanced CRC. These results uncover mechanisms of cell death induced by MLN4924 and suggest that this second-generation proteostasis-disrupting agent may have its most widespread activity in CRC, in combination with irinotecan-containing treatment regimens.
Highlights
By regulating protein turnover, the ubiquitin–proteasome system (UPS) plays a crucial role in regulating cellular proliferation and survival, with its inhibition regarded as an attractive anti-cancer strategy[1]
It has been demonstrated that MLN4924 has an impact on the apoptotic and DNA damage response machinery in cancer cells, the predominant effects of MLN4924 in colorectal cancer (CRC) described to date relate to its effects on cell cycle progression[15,16,17]
It is evident from a number of studies that NEDDylation inhibition induces cancer cell death, with previous studies indicating a role of CRL substrate NOXA and the initiator caspase-818,19, the manner by which cell death occurs remains largely unresolved
Summary
The ubiquitin–proteasome system (UPS) plays a crucial role in regulating cellular proliferation and survival, with its inhibition regarded as an attractive anti-cancer strategy[1]. The first-generation proteasome inhibitor, Bortezomib, demonstrated efficacy in treatment of hematological malignancies; caused significant Grade 3/4 toxicities and demonstrated a lack of Official journal of the Cell Death Differentiation Association. Ferris et al Cell Death Discovery (2020)6:61. MLN4924 is a potent inhibitor of NEDD8 conjugation, with the rapid deNEDDylation of Cullins-1, -2, -3, -4a, -4b, and -5 observed in vitro following treatment[6], resulting in CRL inactivation and subsequent accumulation of CRL substrates[7]. Multiple studies have shown that MLN4924 induces cell death, promotes anti-tumor immunity[8], and inhibits xenograft growth in various pre-clinical models of solid tumors[9]. MLN4924 has demonstrated activity as monotherapy in clinical trials in hematological malignancies, and studies evaluating the combination of MLN4924 in combination with SoC chemotherapies in hematological malignancies, pediatric cancers, and lung cancer are ongoing[10]
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