Combined inhibition synergistically and irreversibly reactivates APC/CCDH1 and induces the degradation of PIN1 and other mitotic proteins, leading to irreversible cell cycle exit, which translates into synergistic anti-tumor activity against triple-negative breast cancer both in immune-compromised and -competent and/or RB-deficient or -proficient mouse models. The gene discussed is RB1; the disease is triple-negative breast carcinoma.