PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer

Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Michela Ranieri, Ke Zhao, Antonio Di Cristofano

Research output: Contribution to journalArticle

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Abstract

Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations. We hypothesized that PI3K activity may facilitate mitotic slippage upon PLK1 inhibition, and thus tested the effect of combining PLK1 and PI3K inhibitors in ATC models, in vitro and in vivo. Treatment with BI6727 and BKM120 resulted in a significant synergistic effect in ATC cells, independent of the levels of AKT activity. Combination of the two drugs enhanced growth suppression at doses for which the single drugs showed no effect, and led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment in PI3Khigh cell lines showed a significant induction of apoptosis. Finally, combined inhibition of PI3K and PLK1 was extremely effective in vivo, in an immunocompetent allograft model of ATC. Our results demonstrate a clear therapeutic potential of combining PLK1 and PI3K inhibitors in anaplastic thyroid tumors.

Original languageEnglish (US)
Pages (from-to)56-65
Number of pages10
JournalCancer Letters
Volume439
DOIs
StatePublished - Dec 28 2018

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Endoreduplication
Phosphatidylinositol 3-Kinases
Apoptosis
Tetraploidy
Drug Combinations
Population
Allografts
Neoplasms
Thyroid Gland
Phosphotransferases
Cell Line
Anaplastic Thyroid Carcinoma
Growth
Pharmaceutical Preparations

Keywords

  • Mitotic slippage
  • Mouse models
  • Thyroid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. / De Martino, Daniela; Yilmaz, Emrullah; Orlacchio, Arturo; Ranieri, Michela; Zhao, Ke; Di Cristofano, Antonio.

In: Cancer Letters, Vol. 439, 28.12.2018, p. 56-65.

Research output: Contribution to journalArticle

De Martino, Daniela ; Yilmaz, Emrullah ; Orlacchio, Arturo ; Ranieri, Michela ; Zhao, Ke ; Di Cristofano, Antonio. / PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. In: Cancer Letters. 2018 ; Vol. 439. pp. 56-65.
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