Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer

Area of Science:

• Molecular Biology
• Cancer Biology
• Genomics

Background:

• Alternative polyadenylation (APA) drives cancer aggressiveness by shortening oncogene 3'UTRs, relieving miRNA repression.
• The therapeutic potential of inhibiting the cleavage and polyadenylation (CPA) machinery in cancer remains underexplored.
• Deregulation of CPA is increasingly recognized as a hallmark of cancer, suggesting it as a source of therapeutic targets.

Purpose of the Study:

• To systematically evaluate the fitness of cancer cell lines upon depletion of CPA factors.
• To identify novel vulnerabilities within the CPA machinery for anticancer therapy development.
• To explore the potential of CPA inhibition (CPAi) as a broad anticancer strategy.

Main Methods:

• Utilized genome-scale CRISPR and RNAi dependency maps from the DepMap project.
• Analyzed the fitness of approximately one thousand cancer cell lines across diverse cancer types.
• Depleted all known core and accessory CPA factors to assess cellular dependency.

Main Results:

• Confirmed core and accessory CPA factors as novel cancer vulnerabilities.
• Demonstrated the potential of CPA inhibition (CPAi) as an anticancer therapeutic approach.
• Identified CPSF1 as a particularly promising drug development candidate due to low dependency scores across cancers, especially in proliferating cells.

Conclusions:

• CPA factors represent actionable targets for novel anticancer therapies.
• CPSF1 is a promising candidate for drug development in CPA inhibition therapy.
• Differential cancer cell line vulnerabilities to CPA factors can inform predictive signatures for personalized CPAi treatment.