2. Academic Validation
  3. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

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

  • J Hematol Oncol. 2020 Feb 22;13(1):13. doi: 10.1186/s13045-020-0846-y.
F Coussy 1 2 3,  R El Botty 4,  M Lavigne 5,  C Gu 5,  L Fuhrmann 5,  A Briaux 6,  L de Koning 7,  A Dahmani 4,  E Montaudon 4,  L Morisset 4,  L Huguet 4,  L Sourd 4,  P Painsec 4,  S Chateau-Joubert 8,  T Larcher 9,  S Vacher 6,  S Melaabi 6,  A Vincent Salomon 5,  E Marangoni 4,  I Bieche 6 10
Affiliations

Affiliations

  • 1 Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France. florence.coussy@curie.fr.
  • 2 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France. florence.coussy@curie.fr.
  • 3 Department of Medical Oncology, Institut Curie, Paris, France. florence.coussy@curie.fr.
  • 4 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France.
  • 5 Department of Biopathology, Institut Curie, Paris, France.
  • 6 Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France.
  • 7 Translational Research Department, RPPA Platform, Institut Curie Research Center, Paris, France.
  • 8 BioPôle Alfort, National Veterinary School of Alfort, Maison Alfort, France.
  • 9 INRA, APEX-PAnTher, Oniris, Nantes, France.
  • 10 Inserm U1016, University Paris Descartes, Paris, France.
PMID: 32087759 DOI: 10.1186/s13045-020-0846-y
Abstract

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.

Keywords

Combination of targeted therapies; MEK inhibitor; Metaplastic breast cancer; PI3K inhibitor.

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