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

Nathan T Ross1,2, Felix Lohmann3, Seth Carbonneau1

  • 1Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Nature Chemical Biology
|December 11, 2019
PubMed

Insights

Researchers identified pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as a novel cancer target. Inhibiting CPSF3 with JTE-607 shows promise for treating acute myeloid leukemia and Ewing's sarcoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Cancer treatment faces challenges from resistance and tumor heterogeneity.
  • Targeting specific cancer pathways remains crucial despite advances in the post-genomic era.

Purpose of the Study:

  • To identify the molecular target of the small molecule JTE-607.
  • To investigate the therapeutic potential of targeting pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) in cancer.

Main Methods:

  • Phenotypic screening and chemical genetics were employed to identify JTE-607's target.
  • The effects of CPSF3 inhibition were analyzed in acute myeloid leukemia (AML) and Ewing's sarcoma cell lines.
  • In vivo efficacy was assessed using mouse xenograft models.

Main Results:

  • CPSF3 was identified as the target of JTE-607.
  • CPSF3 inhibition demonstrated synthetic lethality in a subset of AML and Ewing's sarcoma cells.
  • JTE-607 treatment led to altered downstream effector expression, increased apoptosis, and tumor stasis in vivo.
  • Mechanism involves impaired pre-mRNA release, read-through transcription, and R-loop formation.

Conclusions:

  • CPSF3 is a druggable target for cancer therapy.
  • Inhibition of CPSF3 presents a novel therapeutic strategy for AML and Ewing's sarcoma.
  • Targeting pre-mRNA processing offers a new avenue for cancer intervention.

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