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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.

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