Abstract LB-213: NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer

Abstract

Abstract The NEDD8 conjugation pathway modulates the ubiquitination, stability 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 molecular predictors of response are still missing. We investigated the in vitro sensitivity to pevonedistat in a large panel of molecularly and functionally annotated colorectal cancer (CRC) cell lines, and exploited global gene expression profiles to define a transcriptional predictor. Out of 122 tested cell lines, 16 (13%) displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block and apoptosis. Pevonedistat sensitivity did not significantly correlate with microsatellite instability or mutations in KRAS or BRAF, but was functionally associated with resistance to EGFR pathway blockade. A 184-gene transcriptional predictor generated in cell lines was applied to 87 metastatic CRC clinical samples for which patient-derived xenografts (PDX) were available. For in vivo tests, pevonedistat was provided by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Ltd. In vivo administration of pevonedistat did not affect the growth of any predicted resistant PDX; whereas, it significantly impaired growth of five out of six predicted sensitive models. In human CRC gene expression datasets, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery and early progression under cetuximab treatment. Histological and immunohistochemical analyses revealed that 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 strategy to treat poorly differentiated, clinically aggressive CRC and identify transcriptional and histological response predictors with possible clinical applicability. Citation Format: Gabriele Picco, Francesco Sassi, Claudio Isella, Federica Di Nicolantonio, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico. NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-213.