| Literature DB >> 31819276 |
Nathan T Ross1,2, Felix Lohmann3, Rohan E J Beckwith4, Seth Carbonneau1, Aleem Fazal1, Wilhelm A Weihofen1, Scott Gleim1, Michael Salcius1, Frederic Sigoillot1, Martin Henault1, Sarah H Carl5, Juan B Rodríguez-Molina6, Howard R Miller1, Scott M Brittain1, Jason Murphy1, Mark Zambrowski1, Geoffrey Boynton1, Yuan Wang1, Aye Chen1, Gregory J Molind1, Johannes H Wilbertz5,7, Caroline G Artus-Revel5, Min Jia5,7, Favour A Akinjiyan1, Jonathan Turner3, Judith Knehr3, Walter Carbone3, Sven Schuierer3, John S Reece-Hoyes1, Kevin Xie1, Chitra Saran1, Eric T Williams1, Guglielmo Roma3, Matt Spencer1, Jeremy Jenkins1, Elizabeth L George1, Jason R Thomas1, Gregory Michaud1, Markus Schirle1, John Tallarico1, Lori A Passmore6, Jeffrey A Chao5.
Abstract
The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.Entities:
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Year: 2019 PMID： 31819276 PMCID： PMC7116157 DOI： 10.1038/s41589-019-0424-1
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040