Overcoming Platinum Resistance in Preclinical Models of Ovarian Cancer Using the Neddylation Inhibitor MLN4924

Jazaeri, Amir A.; Shibata, Etsuko; Park, Jonghoon; Bryant, Jennifer; Conaway, Mark R.; Modesitt, Susan C.; Smith, Peter G.; Milhollen, Michael A.; Berger, Allison; Dutta, Anindya

doi:10.1158/1535-7163.mct-12-1028

Cited by 61 publications

(61 citation statements)

References 23 publications

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“…An increasing number of studies have demonstrated that MLN4924 promotes a DNA damage response, cell cycle arrest, apoptosis and senescence in a number of cancer cell types (8,(11)(12)(13)15,22,23). In accordance with these previous studies, the current study observed that MLN4924 promotes apoptosis and the DDR in PTX-resistant NSCLC cells.…”

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

“…Therefore, MLN4924 exhibits potent antitumor activity in numerous types of cancer (14). Notably, previous studies have indicated that MLN4924 overcomes platinum resistance in preclinical models of ovarian cancer (15,16), suggesting that inhibiting neddylation with MLN4924 may be a novel strategy to target drug resistance in cancer.The focus of the present study was to investigate the effects of MLN4924 on PTX-resistant NSCLC cells. The results identified that MLN4924 suppresses the growth of PTX-resistant NSCLC cells by inducing apoptosis and DNA damage.…”

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confidence: 99%

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MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Lin

et al. 2017

Oncol Lett

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Abstract. Acquired resistance to first-line chemotherapeutics, including paclitaxel (PTX), is a primary factor contributing to chemotherapy failure in non-small cell lung cancer (NSCLC) patients. Previous studies have identified that targeting NEDD8-activating enzyme (NAE) with MLN4924 effectively overcomes platinum resistance in preclinical models of ovarian cancer. However, the underlying mechanisms are yet to be fully elucidated. The present study demonstrates that the inhibition of the neddylation pathway with MLN4924 an NAE inhibitor inhibited protein neddylation, inactivated cullin-RING E3 ligase and exhibited a potent antiproliferative effect on PTX-resistant A549 and H460 cells (A549/PTX and H460/PTX). The application of MLN4924 promotes apoptosis and DNA damage in A549/PTX and H460/PTX cells. Additionally, MLN4924 abrogated the 3-dimensional growth potential of these cells and inhibited the formation of the A549/PTX and H460/PTX spheroids. Notably, combining MLN4924 with PTX did not exhibit synergy in PTX-resistant NSCLC cells. Taken together, the results of the current study suggest that MLN4924 may be utilized as an effective strategy for the treatment of PTX-resistant NSCLC. IntroductionLung cancer is a leading cause of cancer mortality globally, in which the predominant subtype of non-small cell lung cancer (NSCLC) represents ~80% of all cases (1). Despite advances in therapy, the overall 5-year survival rate is <15% in patients with NSCLC (2). Currently, conventional chemotherapy remains an important treatment option for patients with NSCLC. Anti-mitotic agents, including docetaxel and paclitaxel (PTX), are predominantly used as chemotherapy regimens for NSCLC (3). However, taxane-based therapy is disadvantaged by the rapid emergence of acquired resistance (4). Therefore, novel therapeutic strategies that overcome the resistance to taxane-based therapy are required.Nedd8 (neural precursor cell expressed, developmentally downregulated 8), a 9-kDa small ubiquitin-like molecule, is involved in protein neddylation initiated by NEDD8 activating enzyme (NAE) (5). Nedd8 serves a role in the activation of the cullin-RING ligases (CRL), also termed SKP1-cullin-F-box (SCF) E3 ligases for its founding member (CRL/SCF) (6), which has been established to be involved in the regulation of multiple DNA replication and repair pathways (7,8). MLN4924 is a recently identified small molecule inhibitor of NAE and is currently in Phase I clinical trials (9,10). By inhibiting neddylation, MLN4924 promotes uncontrolled S-phase DNA replication as well as in the induction of DNA damage and subsequent cell death (11-13). Therefore, MLN4924 exhibits potent antitumor activity in numerous types of cancer (14). Notably, previous studies have indicated that MLN4924 overcomes platinum resistance in preclinical models of ovarian cancer (15,16), suggesting that inhibiting neddylation with MLN4924 may be a novel strategy to target drug resistance in cancer.The focus of the present study was to investigate the effects of MLN4924 on PT...

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Lin

et al. 2017

Oncol Lett

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“…Accumulation of cell cycle regulatory proteins upon MLN4924 treatment was constantly accompanied with DNA damage response, which was partially responsible for the apoptosis and senescence induced upon NEDDylation inhibition (Soucy et al 2009a, b;Mackintosh et al 2013;Jia et al 2011a, b). Given the potency and the unique mechanism of MLN4924 in inducing DNA damage in cancer cells, synergistic interactions between MLN4924 with other DNA-damage-inducing compounds (platinum, cytarabine, Cisplatin, mitomycin C) and radiation will promote its incorporation into current treatment regimens for human malignancies (Nawrocki et al 2013(Nawrocki et al , 2015Yang et al 2012;Wei et al 2012;Kee et al 2012;Jazaeri et al 2013;Garcia et al 2014). These studies highlighted potential incorporation of MLN4924 into current treatment regimens as addition of MLN4924 was shown to sensitize malignant cells to those traditional therapeutic strategies.…”

Section: Skp2mentioning

confidence: 99%

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

Shu-ju

2015

Cytotechnology

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New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin-proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.

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“…11,26). Finally, the discovery that treatment of cancer cells with the neddylation inhibitor pevonedistat (also known as MLN4924) inhibits cancer cell lines and tumors and is associated with significant induction of rereplication demonstrated that rereplication can be induced pharmacologically, and this may have an anticancer activity (27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

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

Vanderdys

Allak

Guessous

et al. 2018

Molecular Cancer Therapeutics

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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.

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Overcoming Platinum Resistance in Preclinical Models of Ovarian Cancer Using the Neddylation Inhibitor MLN4924

Cited by 61 publications

References 23 publications

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

MLN4924 neddylation inhibitor promotes cell death in paclitaxel‑resistant human lung adenocarcinoma cells

Targeting cullin-RING ligases for cancer treatment: rationales, advances and therapeutic implications

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

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