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

Commun Biol. 2021 Jul 12;4(1):862. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Repair / genetics*
  • Drug Combinations
  • Female
  • Humans
  • Mice, Inbred BALB C
  • Mice, SCID
  • Mutation*
  • Phthalazines / administration & dosage
  • Piperazines / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage
  • Pyrrolidines / administration & dosage
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Thymine / administration & dosage
  • Trifluridine / administration & dosage
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Drug Combinations
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrrolidines
  • Tumor Suppressor Protein p53
  • trifluridine tipiracil drug combination
  • Thymine
  • Trifluridine
  • olaparib