ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
NEDD8 Inhibition Overcomes CKS1B-Induced Drug Resistance by Upregulation of p21 in Multiple Myeloma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
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- Inhibiting neddylation: A new strategy for tumor therapy.Journal of pharmaceutical analysis · 2025Review
- Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.European journal of haematology · 2025Review
- Exploring the oncogenic role and prognostic value ofFrontiers in genetics · 2025Article
- Acquired Bortezomib Resistance in Multiple Myeloma: From Mechanisms to Strategy.Current treatment options in oncology · 2024Review
- Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Genes & diseases · 2024Review
- Secretome of Cancer-Associated Fibroblasts (CAFs) Influences Drug Sensitivity in Cancer Cells.Journal of proteome research · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Authentication and validation of key genes in the treatment of atopic dermatitis with Runfuzhiyang powder: combined RNA-seq, bioinformatics analysis, and experimental research.Frontiers in genetics · 2024Article
- A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression.Annals of translational medicine · 2023Article
- Multiple Myeloma With Amplification of Chr1q: Therapeutic Opportunity and Challenges.Frontiers in oncology · 2022Review
- Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism inClinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Identification of novel hub genes associated with lymph node metastasis of head and neck squamous cell carcinoma by completive bioinformatics analysis.Annals of translational medicine · 2021Article
- NEDD9 overexpression: Prognostic and guidance value in acute myeloid leukaemia.Journal of cellular and molecular medicine · 2021Article
- Review
- RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma.Leukemia · 2021Article
- Chromosome 1q21 abnormalities in multiple myeloma.Blood cancer journal · 2021Review
- Predictive value of 1q21 gain in multiple myeloma is strongly dependent on concurrent cytogenetic abnormalities and first-line treatment.American journal of cancer research · 2021Article
- ASF1B Promotes Oncogenesis in Lung Adenocarcinoma and Other Cancer Types.Frontiers in oncology · 2021Article
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Abstract
purposeCKS1B is significantly upregulated in multiple myeloma and associated with poor prognosis. The identification of novel therapies is essential for effective treatment of patients resistant to chemotherapy. The NEDD8 inhibitor MLN4924 selectively targets SCF(Skp2) activation and offers a more specific approach to protein degradation inhibition than total proteasomal inhibition. The goal of this study was to evaluate whether MLN4924 is effective in high CKS1B conditions and identify mechanisms regulating drug potency. EXPERIMENTAL
designBortezomib and MLN4924 sensitivity was assessed through proliferation, viability, clonogenic potential, and senescence induction in cells overexpressing CKS1B. The mechanism for MLN4924 sensitivity was elucidated by immunoblot analysis of SCF(skp) substrates and confirmed by shRNA knockdown. The clinical relevance of the NEDD8 pathway was examined in gene expression profiles (GEP) derived from healthy people, patients with monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma.
resultsCells overexpressing CKS1B were resistant to bortezomib but sensitive to MLN4924. Treatment of CKS1B-overexpressing cells with MLN4924 decreased proliferation, clonogenicity, and induced senescence. MLN4924, but not bortezomib, induced stabilization of p21 and knockdown of p21 resulted in loss of MLN4924 sensitivity. Patients with MGUS and multiple myeloma exhibited increased expression of NEDD8 pathway genes relative to normal plasma cells. Multiple myeloma patients with high NEDD8 expression were linked to bortezomib resistance in clinical trials, and had inferior outcomes.
conclusionsOur data demonstrate that cells with elevated CKS1B expression are resistant to bortezomib but sensitive to MLN4924 and offer a mechanism through the stabilization of p21. These findings provide rationale for targeting the NEDD8 pathway in multiple myeloma patients exhibiting elevated expression of CKS1B. Clin Cancer Res; 21(24); 5532-42. ©2015 AACR.
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