Targeting PRMTs Creates Vulnerability of DNA Double‐Stand Break Repair Pathways, and Potentiates Chemotherapy Efficacy in TNBC

Patients with triple-negative breast cancer (ER^-, PR^-, and HER2^-) are routinely treated with chemotherapies that induce DNA damage. However, around 30% of patients display resistance, owing largely to increased DNA repair mechanisms, upregulated to allow cancer cells to escape such therapies. PRMT1 and PRMT5, the two main protein arginine methyltransferases, are involved in several biological pathways, including DNA repair signaling, where they contribute to ensuring DNA integrity. We then speculated that targeting their enzymatic activity may sensitize TNBC cells to chemotherapeutic agents inducing DNA double-strand breaks. Here, we showed that PRMT1 and PRMT5 are recruited to DNA double-strand breaks upon doxorubicin or carboplatin treatment, two chemotherapies currently used to treat TNBC patients, and are preferentially involved in the homologous recombination pathway. By combining PRMT inhibitors with doxorubicin or carboplatin, we increased DNA double-strand breaks and impaired TNBC cell proliferation and clonogenicity in vitro and sensitized patient-derived models of TNBC to carboplatin treatment. These preclinical data provide a rationale for the clinical evaluation of PRMT inhibitors as combinatorial agents to improve chemotherapy efficacy for TNBC patients.