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

• Published in: Journal of hematology and oncology Vol. 13; no. 1; pp. 13 - 10
• Main Authors: Coussy, F, El Botty, R, Lavigne, M, Gu, C, Fuhrmann, L, Briaux, A, de Koning, L, Dahmani, A, Montaudon, E, Morisset, L, Huguet, L, Sourd, L, Painsec, P, Chateau-Joubert, S, Larcher, T, Vacher, S, Melaabi, S, Salomon, A Vincent, Marangoni, E, Bieche, I
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.02.2020; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents - therapeutic use; Arrays; Biotechnology industries; Breast cancer; Breast tumors; Cancer treatment; Chemotherapy; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Combination of targeted therapies; Comparative analysis; Gene expression; Genes; Genomes; Genomics; Hematology; Humans; Kinases; Life Sciences; MEK inhibitor; MEK inhibitors; Metaplastic breast cancer; Metastasis; Mice, Nude; Middle Aged; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Mutation - drug effects; Oncology; Patients; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; PI3K inhibitor; Protein Kinase Inhibitors - therapeutic use; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Remission; Short Report; Signal Transduction - drug effects; Stem cells; TOR Serine-Threonine Kinases - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Tumors; Xenograft Model Antitumor Assays; Xenografts; United States; France; MEK inhibitor; Metaplastic breast cancer; Combination of targeted therapies; PI3K inhibitor
• DOI: 10.1186/s13045-020-0846-y
• ISSN: 1756-8722

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. 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. 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. 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.