Inhibition of PSF Activity Overcomes Resistance to Treatment in Cancers Harboring Mutant p53

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mutations in TP53 tumor suppressor genes are common in aggressive cancers, leading to dysfunctional p53.
• Polypyrimidine tract-binding protein-associated splicing factor (PSF) drives cancer progression by affecting oncogene expression via epigenetic and splicing modulation.
• Targeting PSF is a potential therapeutic strategy for cancers with mutated TP53.

Purpose of the Study:

• To identify and characterize novel inhibitors of PSF.
• To evaluate the efficacy of a novel PSF inhibitor, C-30, in preclinical cancer models, particularly those with mutant p53 and therapy resistance.
• To elucidate the mechanism of action of C-30 in cancer cells.

Main Methods:

• Screening of a small-molecule library to identify PSF inhibitors.
• Synthesis and characterization of C-30, a novel analog of compound No. 10-3.
• In vitro assessment of C-30's effects on cancer cell growth, apoptosis, and gene expression.
• In vivo studies to evaluate C-30's anti-tumor activity and impact on p53 target genes.
• Analysis of PSF and p53 binding regions and histone acetylation.

Main Results:

• C-30 was identified as a potent inhibitor of PSF.
• C-30 specifically suppressed the growth and induced apoptosis in mutant p53-bearing and therapy-resistant cancer cells.
• C-30 treatment led to the activation of p53-regulated genes and increased histone acetylation in resistant cancer cells.
• In vivo, C-30 impaired tumor growth and upregulated p53 target gene expression.

Conclusions:

• C-30 demonstrates significant anti-cancer activity, particularly in therapy-resistant cancers with mutant p53.
• The mechanism involves PSF inhibition, leading to effects similar to p53 reactivation.
• Inhibition of PSF by C-30 represents a promising therapeutic approach for aggressive and treatment-resistant cancers.