Identification, validation, and targeting of the mutant p53-PARP-MCM chromatin axis in triple negative breast cancer

Abstract

Personalized medicine: Mutated tumors respond to therapy Mutations in the p53 tumor suppressor gene could offer a predictive biomarker of response to certain drugs in triple-negative breast cancer. Jill Bargonetti from Hunter College in New York, USA, and colleagues showed that mutant p53, which is expressed in more than 80% of patients with triple-negative breast cancer, interacts with and regulates hundreds of proteins, including those found in a complex needed for DNA replication. Members of this complex, called the minichromosome maintenance protein complex, interact with mutant p53—but less with wild-type p53. Bargonetti’s team targeted this pathway in mutated breast cancer cells with the PARP inhibitor talazoparib and the chemotherapeutic agent temozolomide. They observed synergistic cell killing with the two drugs, but only when the minichromosome maintenance protein complex was working and when p53 was mutated. These findings point toward a new strategy for personalizing therapy.