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

Malhab, Lara J Bou; Descamps, Simon; Delaval, Bénédicte; Xirodimas, Dimitris P.

doi:10.1038/srep37775

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…Importantly, no obvious toxicity was observed in all the treatment groups. Because of its safety and efficacy towards a variety of malignancies, MLN4924 has been advanced to several phase I and one phase II clinical trials for solid tumors and hematologic malignancies [35,36]. While there were less trials of SCH 900776, multiple other Chk1 inhibitors were being tested in the clinical setting [37].…”

Section: Discussionmentioning

confidence: 99%

Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer

Song

Rong

et al. 2018

Cell Cycle

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MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication. In vivo study on a xenograft PC mouse model also showed that SCH 900776 increased the efficacy of MLN4924. We also evaluated the level of NEDD8-activating enzyme (NAE), the direct target of MLN4924, and found that NAE level was elevated in PC tissues compared with normal pancreas, but was irrelevant with prognosis. Our findings provide the preclinical evidence and the rationale of the combination therapy of MLN4924 with SCH 900776 or other Chk1 inhibitors to treat PC.

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Section: Discussionmentioning

confidence: 99%

Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer

Song

Rong

et al. 2018

Cell Cycle

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“…On the other hand, JAB1 is solely responsible for catalyzing the removal of NEDD8 from CRLs, thus deactivating CRLs and maintaining their cellular homeostasis ( Figure 7A ) ( 32 ). In recent years, the NEDDylation pathway has emerged as an attractive therapeutic target for cancer treatment ( Figure 7A ) ( 33 – 35 ). Indeed, MLN4924, a specific inhibitor of NAE1, is currently in clinical trials for the treatment of various cancers ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

“…CRL homeostasis is tightly regulated by NEDDylation ( Figure 7A ). A small molecule inhibitor of NAE1, MLN4924 ( Figure 7A ), inhibited tumor xenografts in mice, and is currently in many Phase I and II clinical trials for the treatment of hematologic and other cancers, as well as a phase III clinical trial in combination with azacitidine for the treatment of acute myeloid leukemia, but is associated with severe side effects, serious adverse events, and drug resistance ( 33 – 36 , 40 ). CSN5i-3 is a recently developed and highly specific small molecule inhibitor of JAB1 ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

et al. 2020

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Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. J un a ctivation domain b inding protein 1 ( JAB1 ) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1 -knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1 -knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers.

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“…Elevated basal p21 may consequently be a marker for resistance of cSCC cells to MLN4924. Wild-type p53 can protect against MLN4924 in part through p21 induction; however, p53 is mutated in all cSCC lines (Lin et al, 2010;Malhab et al, 2016). Given the particular efficacy of CDT2 knockdown in killing cSCC cells, the differences in modulation of CRL4 CDT2 substrates observed with CDT2 depletion and MLN4924, and the effects of MLN4924 on multiple pathways, it would be of interest to develop CDT2-specific inhibitors.…”

Section: Cullin-ring Ligase (Crl) 4 Cdt2mentioning

confidence: 99%

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

McHugh

Fernandes

Chinner

et al. 2020

Journal of Investigative Dermatology

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We performed a small interfering RNA screen to identify targets for cutaneous squamous cell carcinoma (cSCC) therapy in the ubiquitin/ubiquitin-like system. We provide evidence for selective anti-cSCC activity of knockdown of the E3 ubiquitin ligase MARCH4, the ATPase p97/VCP, the deubiquitinating enzyme USP8, the cullin-RING ligase (CRL) 4 substrate receptor CDT2/DTL, and components of the anaphase-promoting complex/ cyclosome (APC/C). Specifically attenuating CRL4 CDT2 by CDT2 knockdown can be more potent in killing cSCC cells than targeting CRLs or CRL4s in general by RBX1 or DDB1 depletion. Suppression of the APC/C or forced APC/C activation by targeting its repressor EMI1 are both potential therapeutic approaches. We observed that cSCC cells can be selectively killed by small-molecule inhibitors of USP8 (DUBs-IN-3/compound 22c) and the NEDD8 E1 activating enzyme/CRLs (MLN4924/pevonedistat). A substantial proportion of cSCC cell lines are very highly MLN4924-sensitive. Pathways that respond to defects in proteostasis are involved in the anti-cSCC activity of p97 suppression. Targeting USP8 can reduce the expression of growth factor receptors that participate in cSCC development. EMI1 and CDT2 depletion can selectively cause DNA re-replication and DNA damage in cSCC cells.

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

Cited by 19 publications

References 30 publications

Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer

Chk1 inhibitor SCH 900776 enhances the antitumor activity of MLN4924 on pancreatic cancer

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

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