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Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2016 Oct 22; Vol. 109 (2). Date of Electronic Publication: 2016 Oct 22 (Print Publication: 2017). - Publication Year :
- 2016
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Abstract
- Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing.<br />Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry. Associations between pevonedistat sensitivity and CRC molecular features were assessed by Student's t test. A 184-gene transcriptional predictor was generated in cell lines and applied to 87 metastatic CRC samples for which patient-derived xenografts (PDXs) were available. In vivo reponse to pevonedistat was assessed in PDX models (≥5 mice per group). All statistical tests were two-sided.<br />Results: Sixteen (13.1%) cell lines displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block, and increased apoptosis. Pevonedistat sensitivity did not statistically significantly correlate with microsatellite instability or mutations in KRAS or BRAF and was functionally associated with low EGFR pathway activity. While ineffective on predicted resistant PDXs, in vivo administration of pevonedistat statistically significantly impaired growth of five out of six predicted sensitive models (P < .01). In samples from CRC patients, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.34 to 4.62, P = .003) and early progression under cetuximab treatment (HR = 3.59, 95% CI = 1.60 to 8.04, P < .001). Histological and immunohistochemical analyses revealed that the pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma.<br />Conclusions: These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC.<br /> (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Adenocarcinoma, Mucinous genetics
Adenocarcinoma, Mucinous pathology
Animals
Antineoplastic Agents therapeutic use
Apoptosis drug effects
CDX2 Transcription Factor genetics
Cadherins genetics
Cell Line, Tumor
Cell Proliferation drug effects
Cetuximab therapeutic use
Colorectal Neoplasms genetics
Colorectal Neoplasms pathology
Cyclopentanes therapeutic use
DNA Replication drug effects
Disease-Free Survival
Drug Resistance, Neoplasm genetics
Female
Homeodomain Proteins genetics
Humans
Keratin-20 genetics
Mice
NEDD8 Protein
Neoplasm Grading
Neoplasm Transplantation
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins p21(ras) genetics
Pyrimidines therapeutic use
Signal Transduction drug effects
Ubiquitins metabolism
Adenocarcinoma, Mucinous drug therapy
Antineoplastic Agents pharmacology
Colorectal Neoplasms drug therapy
Cyclopentanes pharmacology
Pyrimidines pharmacology
Transcriptome
Ubiquitins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 109
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 27771609
- Full Text :
- https://doi.org/10.1093/jnci/djw209