title: Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC.
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Gabriele
authors: G
authors: Picco
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Consalvo
authors: C
authors: Petti
authors: Department of Oncology, University of Torino, Torino, Italy.
authors: Francesco
authors: F
authors: Sassi
authors: Department of Oncology, University of Torino, Torino, Italy.
authors: Katia
authors: K
authors: Grillone
authors: Department of Oncology, University of Torino, Torino, Italy.
authors: Giorgia
authors: G
authors: Migliardi
authors: Department of Oncology, University of Torino, Torino, Italy.
authors: Teresa
authors: T
authors: Rossi
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Claudio
authors: C
authors: Isella
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Federica
authors: F
authors: Di Nicolantonio
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.
authors: Ivana
authors: I
authors: Sarotto
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Medical Sciences, University of Torino, Torino, Italy.
authors: Anna
authors: A
authors: Sapino
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Alberto
authors: A
authors: Bardelli
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Livio
authors: L
authors: Trusolino
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Andrea
authors: A
authors: Bertotti
authors: Candiolo Cancer Institute-FPO IRCCS, Candiolo, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors: Enzo
authors: E
authors: Medico
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000071616:CDX2 Transcription Factor / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D004261:DNA Replication / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D053554:Keratin-20 / Q000235:genetics; D051379:Mice; D000075687:NEDD8 Protein; D060787:Neoplasm Grading; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C490584:CDH17 protein, human; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D015820:Cadherins; D003517:Cyclopentanes; D018398:Homeodomain Proteins; C117307:KRAS protein, human; C507499:KRT20 protein, human; D053554:Keratin-20; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; C539933:pevonedistat