2. Academic Validation
  3. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma

  • Nat Chem Biol. 2020 Jan;16(1):50-59. doi: 10.1038/s41589-019-0424-1.
Nathan T Ross  # 1 2,  Felix Lohmann  # 3,  Seth Carbonneau 1,  Aleem Fazal 1,  Wilhelm A Weihofen 1,  Scott Gleim 1,  Michael Salcius 1,  Frederic Sigoillot 1,  Martin Henault 1,  Sarah H Carl 4,  Juan B Rodríguez-Molina 5,  Howard R Miller 1,  Scott M Brittain 1,  Jason Murphy 1,  Mark Zambrowski 1,  Geoffrey Boynton 1,  Yuan Wang 1,  Aye Chen 1,  Gregory J Molind 1,  Johannes H Wilbertz 4 6,  Caroline G Artus-Revel 4,  Min Jia 4 6,  Favour A Akinjiyan 1,  Jonathan Turner 3,  Judith Knehr 3,  Walter Carbone 3,  Sven Schuierer 3,  John S Reece-Hoyes 1,  Kevin Xie 1,  Chitra Saran 1,  Eric T Williams 1,  Guglielmo Roma 3,  Matt Spencer 1,  Jeremy Jenkins 1,  Elizabeth L George 1,  Jason R Thomas 1,  Gregory Michaud 1,  Markus Schirle 1,  John Tallarico 1,  Lori A Passmore 5,  Jeffrey A Chao 4,  Rohan E J Beckwith  # 7
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 2 Vertex Pharmaceuticals, Boston, MA, USA.
  • 3 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 4 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 5 Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
  • 6 University of Basel, Basel, Switzerland.
  • 7 Novartis Institutes for BioMedical Research, Cambridge, MA, USA. rohan.beckwith@novartis.com.
  • # Contributed equally.
PMID: 31819276 DOI: 10.1038/s41589-019-0424-1
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.

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