1. Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer.
- Author
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Picco G, Petti C, Sassi F, Grillone K, Migliardi G, Rossi T, Isella C, Di Nicolantonio F, Sarotto I, Sapino A, Bardelli A, Trusolino L, Bertotti A, and Medico E
- 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
- 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., 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., 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., Conclusions: These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2016
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