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Metaplastic breast cancer (MpBC) is a rare and highly aggressive subset accounting for <5% of all BCs. Clinically, MpBCs exhibit the most dismal prognosis of all BC subtypes, with a median survival rate of 8 months in patients with metastatic disease. The main therapeutic option for MpBC remains standard chemotherapy, despite known resistance to most cytotoxic drugs. We recently reported that ~40% of MpBC patient samples display a gain-of-function oncogenic mutation (A14V) in ribosomal protein RPL39, which is responsible for treatment resistance, cancer stem cell self-renewal, and lung metastases. We also showed that high RPL39 levels were associated with worse survival in patients with MpBC. Collectively, these findings support the rationale of targeting this ubiquitous genetic marker in MpBC. This study was aimed to design an innovative targeted therapy against RPL39 by combining a small …