CPSF3-dependent pre-mRNA processing as a druggable node in AML 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.