Selective therapeutic strategy for p53-deficient cancer by targeting dysregulation in DNA repair

Justin Zonneville,Megan Melnick,Mohammed M Alruwaili,Andrei V Bakin,Christos Fountzilas,Brandon Smith,Kevin H Eng,Moyi Wang,Renuka Iyer,Thomas Melendy,Ben Ho Park

doi:10.1038/s42003-021-02370-0

Abstract

Breast carcinomas commonly carry mutations in the tumor suppressor p53, although therapeutic efforts to target mutant p53 have previously been unfruitful. Here we report a selective combination therapy strategy for treatment of p53 mutant cancers. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER. This defect rendered accumulation of DNA damage in p53 mutant cells upon treatment with deoxyuridine analogues. Notably, inhibition of poly (ADP-ribose) polymerase (PARP) greatly enhanced this response, whereas normal cells responded with activation of the p53-p21 axis and cell cycle arrest. Inactivation of either p53 or p21/CDKN1A conferred the p53 mutant phenotype. Preclinical animal studies demonstrated a greater anti-neoplastic efficacy of the drug combination (deoxyuridine analogue and PARP inhibitor) than either drug alone. This work illustrates a selective combination therapy strategy for p53 mutant cancers that will improve survival rates and outcomes for thousands of breast cancer patients.

Highlights

Breast carcinomas commonly carry mutations in the tumor suppressor p53, therapeutic efforts to target mutant p53 have previously been unfruitful
We explored the expression of replication-related genes (RRGs) in breast cancer (BC) subtypes using The Cancer Genome Atlas (TCGA) data[21]
Genomic data showed that triplenegative breast cancers (TNBCs)/Basal-like cancers (TNBC thereafter) exhibit high expression of RRGs (S- and M-phase cell cycle; t-test P < 0.001), indicating elevated replication activity

Summary

Introduction

Breast carcinomas commonly carry mutations in the tumor suppressor p53, therapeutic efforts to target mutant p53 have previously been unfruitful. Genomic data revealed that p53 mutant cancers exhibit high replication activity and express high levels of the Base-Excision Repair (BER) pathway, whereas experimental testing showed substantial dysregulation in BER. This defect rendered accumulation of DNA damage in p53 mutant cells upon treatment with deoxyuridine analogues. We discovered substantial dysregulation in base excision repair (BER) in p53 mutant cancer cells that lead to accumulation of DNA damage upon treatment with nucleotide analogues. Based on this finding, we developed a combination therapeutic regimen that selectively targets p53-mutant breast cancer. This study illustrates a selective synthetic lethality strategy for the treatment of breast cancer by means of exploiting DNA repair dysfunction of p53 mutant cancer cells

Methods

Results

Conclusion