Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

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