The use of the NEDD8 inhibitor MLN4924 (Pevonedistat) in a cyclotherapy approach to protect wild-type p53 cells from MLN4924 induced toxicity.

Lara J Bou Malhab,Dimitris P Xirodimas,Benedicte Delaval,Simon Descamps

doi:10.1038/srep37775

Lara J Bou Malhab, Dimitris P Xirodimas + Show 2 more

Open Access

https://doi.org/10.1038/srep37775

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Abstract

Targetting the ubiquitin pathway is an attractive strategy for cancer therapy. The inhibitor of the ubiquitin-like molecule NEDD8 pathway, MLN4924 (Pevonedistat) is in Phase II clinical trials. Protection of healthy cells from the induced toxicity of the treatment while preserving anticancer efficacy is a highly anticipated outcome in chemotherapy. Cyclotherapy was proposed as a promising approach to achieve this goal. We found that cytostatic activation of p53 protects cells against MLN4924-induced toxicity and importantly the effects are reversible. In contrast, cells with mutant or no p53 remain sensitive to NEDD8 inhibition. Using zebrafish embryos, we show that MLN4924-induced apoptosis is reduced upon pre-treatment with actinomycin D in vivo. Our studies show that the cellular effects of NEDD8 inhibition can be manipulated based on the p53 status and that NEDD8 inhibitors can be used in a p53-based cyclotherapy protocol to specifically target cancer cells devoid of wild type p53 function, while healthy cells will be protected from the induced toxicity.

Highlights

Protein modification with the ubiquitin-like molecule (Ubl) NEDD8 is emerging as an important regulatory pathway[1,2]
We found that pre-treatment of wild type p53 cells with low doses of actinomycin D (LDActD) or Nutlin-3 completely protects these cells against the cytotoxic effects of MLN4924
At low doses of actinomycin D (1–4 nM, LDActD), p53 activation causes a cytostatic effect through G1/G2 cell cycle arrest[15]

Summary

Introduction

Protein modification with the ubiquitin-like molecule (Ubl) NEDD8 (protein NEDDylation) is emerging as an important regulatory pathway[1,2]. Treatment of tumour cells (breast, pancreatic, lung, ovarian, melanoma, B-cell like lymphomas) with MLN4924 induces apoptosis, and in vivo MLN4924 shows anti-tumour activity in mice harbouring human xenografts for solid and hematologic tumours[8,9]. These data suggested the NEDD8 pathway as a promising therapeutic target and MLN4924/ Pevonedistat is in Phase II cancer clinical trials[10], https://clinicaltrials.gov/ct2/show/NCT02610777?term=pevonedistat&rank=1). A promising strategy called cyclotherapy, which aims at protecting normal tissues from chemotherapy side effects, has been developed It is based on both the cell cycle and the status of the p53 tumour suppressor[12,13,14,15,16]. Cdt[1] is required for replication firing but is degraded by CRLs, in S phase (cullin4A-DDB1) or throughout the cell cycle (cullin1-Skp2) to prevent re-replication[20]

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