The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

Abstract

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virusnegative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.

Neural precursor cell expressed, developmentally downregulated 8 promotes tumor progression and predicts poor prognosis of patients with bladder cancer

“…For instance, MLN4924, a small molecule inhibitor of NAE, has been advanced into phase I clinical trials for certain solid tumors . MLN4924 shows antitumor activities in numerous types of cancer . In bladder cancer, MLN4924 could suppress the proliferation of tumor cells in vitro and in vivo .…”

“…24 MLN4924 shows antitumor activities in numerous types of cancer. 12,14,[25][26][27] In bladder cancer, MLN4924…”

“…Hence, inhibition of protein neddylation has become an attractive anticancer strategy . Neddylation inhibitor such as MLN4924 was found to play important roles in inhibiting tumor proliferation and metastasis . In bladder cancer, MLN4924 suppressed proliferation and migration of tumors in in vitro and in vivo experiments .…”

“…10,11 Neddylation inhibitor such as MLN4924 was found to play important roles in inhibiting tumor proliferation and metastasis. [12][13][14] In bladder cancer, MLN4924 suppressed proliferation and migration of tumors in in vitro and in vivo experiments. 15 However, the role of NEDD8 in bladder cancer remains unknown.…”

Dynamics of replication origin over-activation

“…Partial genome re-replication can also be caused by inhibition of DOT1L, a methyltransferase which catalyzes the demethylation of histone H3 on lysine 79 (H3K79Me2), thereby removing a histone modification typically associated with a group of replication origins 27 . Because massive re-replication can drive cell death specifically in checkpointcompromised cancer cells, both CDT1 stabilization by inactivation of ubiquitin-mediated degradation and inhibition of DOT1L are currently being explored as novel anti-cancer therapeutic strategies [28][29][30][31][32][33] .Given that genome re-replication is a common avenue to genomic instability and considering its potential as a strategy for chemotherapy, it is important to understand in detail its mechanics and downstream consequences. Here, we report that re-replication exhibits aberrant replication fork dynamics and occurs more slowly than the routine genome duplication that takes place during normal growth.…”