@article{30adfdd0f544479cbe52c9650fa806e1,
title = "Synthetic lethality screening highlights colorectal cancer vulnerability to concomitant blockade of nedd8 and egfr pathways",
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{\textquoteright} 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.",
keywords = "CRC, EGFR pathway, NEDD8, Pevonedistat, Synthetic lethality screening",
author = "Federica Invrea and Simona Punzi and Consalvo Petti and Rosalba Minelli and Peoples, {Michael D.} and Bristow, {Christopher A.} and Valentina Vurchio and Alessia Corrado and Alberto Bragoni and Caterina Marchi{\`o} and Andrea Bertotti and Livio Trusolino and Alberto Bardelli and Claudio Isella and Alessandro Carugo and Draetta, {Giulio F.} and Enzo Medico",
note = "Funding Information: Funding: This research was funded by: FONDAZIONE AIRC under 5 per Mille 2018—ID. 21091 program–P.I. Bardelli Alberto (A.Ba.) and Group Leader Medico Enzo (E.M.), Trusolino Livio (L.T.), Bertotti Andrea (A.Be.), and Marchi{\`o} Caterina (C.M.); MAECI PGR00815 to E.M.; AIRC IG 2017 No. 20697 to A.Be.; European Research Council Consolidator Grant 724748, BEAT to A.Be.; My First AIRC Grant 19047 to C.I.; Ministero della Salute GR‐2016‐02362726 to C.I.; AIRC Investi‐ gator Grant 22802 to L.T.; International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) to L.T. and A.Ba.; H2020 grant agreement no. 754923 COLOSSUS to L.T.; Fondazione Piemontese per la Ricerca sul Cancro‐ONLUS, 5 × 1000 Ministero della Salute 2014, 2015 and 2016 to L.T. and E.M.; Grant n. 710632‐80‐120294‐19—TRACTION Academic Collaborations‐Philanthropy Funds to G.F.D.; AIRC under IG 2018—ID. 21923 project—P.I. Bardelli Alberto to A.Ba; BiLiGeCT—Progetto PON ARS01_00492 to A.Ba; E.M., A.Be. and L.T. are members of the EurOPDX Consortium. Funding Information: This research was funded by: FONDAZIONE AIRC under 5 per Mille 2018?ID. 21091 program?P.I. Bardelli Alberto (A.Ba.) and Group Leader Medico Enzo (E.M.), Trusolino Livio (L.T.), Bertotti Andrea (A.Be.), and Marchi? Caterina (C.M.); MAECI PGR00815 to E.M.; AIRC IG 2017 No. 20697 to A.Be.; European Research Council Consolidator Grant 724748, BEAT to A.Be.; My First AIRC Grant 19047 to C.I.; Ministero della Salute GR?2016?02362726 to C.I.; AIRC Investigator Grant 22802 to L.T.; International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) to L.T. and A.Ba.; H2020 grant agreement no. 754923 COLOSSUS to L.T.; Fondazione Piemontese per la Ricerca sul Cancro?ONLUS, 5 ? 1000 Ministero della Salute 2014, 2015 and 2016 to L.T. and E.M.; Grant n. 710632?80?120294?19?TRACTION Academic Collaborations?Philanthropy Funds to G.F.D.; AIRC under IG 2018?ID. 21923 project?P.I. Bardelli Alberto to A.Ba; BiLiGeCT?Progetto PON ARS01_00492 to A.Ba; E.M., A.Be. and L.T. are members of the EurOPDX Consortium.We thank Carlotta Cancelliere, Daniela Cantarella, and Stefania Giove for technical assistance, and Simona Destefanis for administrative support. We thank Alberto Puliafito for advice and discussions. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = aug,
day = "1",
doi = "10.3390/cancers13153805",
language = "English (US)",
volume = "13",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "15",
}