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Background Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. Methods We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. Results In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA , AKT1 , BRAF , and FGFR4 . Conclusion The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.