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Synthetic Lethality Screening Highlights Colorectal Cancer Vulnerability to Concomitant Blockade of NEDD8 and EGFR Pathways

Authors :
Federica Invrea
Simona Punzi
Consalvo Petti
Rosalba Minelli
Michael D. Peoples
Christopher A. Bristow
Valentina Vurchio
Alessia Corrado
Alberto Bragoni
Caterina Marchiò
Andrea Bertotti
Livio Trusolino
Alberto Bardelli
Claudio Isella
Alessandro Carugo
Giulio F. Draetta
Enzo Medico
Source :
Cancers, Vol 13, Iss 15, p 3805 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Colorectal cancer (CRC) is a heterogeneous disease showing significant variability in clinical aggressiveness. Primary and acquired resistance limits the efficacy of available treatments, and identification of effective drug combinations is needed to further improve patients’ outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a “drop-out” loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. These results unveil possible therapeutic opportunities in specific CRC clinical settings.

Details

Language :
English
ISSN :
20726694
Volume :
13
Issue :
15
Database :
Directory of Open Access Journals
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
edsdoj.fa46ce1689446d78a3d26329e199e47
Document Type :
article
Full Text :
https://doi.org/10.3390/cancers13153805