Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells

Abstract

Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target. In our study, we demonstrate that MLN4924 can be used as a potent radiosensitizer in hormone-resistant prostate cancer cells. We found that MLN4924 inhibited cullin neddylation and sensitized prostate cancer cells to irradiation (IR). Mechanistically, MLN4924 enhanced IR-induced G2 cell-cycle arrest, by inducing accumulation of WEE1/p21/p27, three well-known CRL substrates. Importantly, siRNA knockdown of WEE1/p21/p27 partially abrogated MLN4924-induced G2 cell-cycle arrest, indicating a causal role of WEE1/p21/p27 in MLN4924-induced radiosensitization. Further mechanistic studies revealed that induction of DNA damage and apoptosis also contributed to MLN4924 radiosensitization in hormone-resistant prostate cancer cells. Our findings lay the foundation for future application of MLN4924 as a potential radiosensitizer in hormone refractory prostate cancer (HRPC).

Neddylation inhibitor MLN4924 induces G2 cell cycle arrest, DNA damage and sensitizes esophageal squamous cell carcinoma cells to cisplatin

“…The present study demonstrated that MLN4924 could induce G 2 cell cycle arrest in ESCC cells. At the same time, MLN4924 significantly enhanced the protein stability of p21, p27 and Wee1, which is in accordance with previous studies (9,15), where they indicate that all of the 3 proteins serve an important function in MLN4924-induced G 2 cell cycle arrest (23).…”

“…Previously, MLN4924 exhibited attractive pharmacodynamic effects in phase I studies in patients with advanced solid tumors, relapsed/refractory lymphoma and metastatic melanoma for its tolerable safety profile (17)(18)(19). MLN4924 may function as a novel chemosensitizer or radiosensitizer in multiple types of cancer (20)(21)(22)(23)(24). These results indicate that targeting the neddylation pathway may represent an attractive anticancer strategy, either alone or in combination with other therapies.…”

Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

“…Many RB therapies induce DNA damage 1 and MLN4924 synergizes with DNA damaging agents 30 , including radiation [31][32][33] . Our in vivo study showed IVT MLN4924 was effective, however in the schedule used we did not observe any complete responses (CR), therefore residual tumor cells would likely regrow.…”

Targeting E3 ubiquitin ligases to sensitize cancer radiation therapy

“…al. that silencing of UBC12, the NEDD8 E2 enzyme, sensitizes prostate cancer cells to radiation . In 2009, a small‐molecule inhibitor called MLN4924 was developed to specifically target the neddylation E1 enzyme, NAE, potently blocking cullin neddylation and activation .…”