Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation

摘要

Triple negative breast cancer (TNBC) is an aggressive subset for which effective therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc metallochaperones (ZMCs) are a new class of anti-cancer drugs that specifically reactivate zinc-deficient mutant p53 by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53^R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using murine breast cancer models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival of mice bearing tumors harboring the zinc-deficient Trp53^R172H allele but not the Trp53^−/− allele. We synthesized a new formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for p53^R172H tumor growth inhibition. In conclusion, we have validated preclinically a new therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53.