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
  • 1. Unit of Pharmacogenomics, Department of Genetics, Institut Curie, Paris, France. [email protected].
  • 2. Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France. [email protected].
  • 3. Department of Medical Oncology, Institut Curie, Paris, France. [email protected].
  • 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.
Products