Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs

M. Orditura, C. M. Della Corte, A. Diana, V. Ciaramella, E. Franzese, V. Famiglietti, I. Panarese, R. Franco, A. Grimaldi, A. Lombardi, M. Caraglia, A. Santoriello, E. Procaccini, E. Lieto, E. Maiello, F. De Vita, F. Ciardiello, F. Morgillo

Research output: Contribution to journalArticle

Abstract

Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.

Original languageEnglish
Pages (from-to)165-171
Number of pages7
JournalBreast
Volume41
DOIs
Publication statusPublished - Oct 1 2018

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Keywords

  • AKT
  • Breast cancer
  • Ex vivo models
  • Ipatasertib
  • Taselisib
  • Three-dimensional cell cultures

ASJC Scopus subject areas

  • Surgery

Cite this

Orditura, M., Della Corte, C. M., Diana, A., Ciaramella, V., Franzese, E., Famiglietti, V., Panarese, I., Franco, R., Grimaldi, A., Lombardi, A., Caraglia, M., Santoriello, A., Procaccini, E., Lieto, E., Maiello, E., De Vita, F., Ciardiello, F., & Morgillo, F. (2018). Three dimensional primary cultures for selecting human breast cancers that are sensitive to the anti-tumor activity of ipatasertib or taselisib in combination with anti-microtubule cytotoxic drugs. Breast, 41, 165-171. https://doi.org/10.1016/j.breast.2018.08.002