Journal Article

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

Gu, C., Painsec, P., Marangoni, E., Vacher, S., Bieche, I., Sourd, L., Montaudon, E., Melaabi, S., Lavigne, M., Huguet, L., Chateau-Joubert, S., Dahmani, A., El Botty, R., Salomon, A. Vincent, Coussy, F., Briaux, A., Morisset, L., de Koning, L., Larcher, T., Fuhrmann, L.

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Adult / Aged / Aged, 80 and over / Animals / Antineoplastic Agents - therapeutic use / Arrays / Biotechnology industries / Breast cancer / Breast tumors / Cancer Research / 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 / Medicine / Medicine & Public Health / 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