Abstract 1068: Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer
Abstract Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from the time of diagnosis. Molecular changes that characterize ATC have been recently well defined and involve most often p53 mutations, and activation of PI3K, RAS and BRAF...
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| Published in: | Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.1068-1068 |
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| Main Authors: | , , , |
| Format: | Article |
| Language: | eng |
| Online Access: | Get full text |
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| Summary: | Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from the time of diagnosis. Molecular changes that characterize ATC have been recently well defined and involve most often p53 mutations, and activation of PI3K, RAS and BRAF. PLK1, an essential mitotic regulator, has been found overexpressed in ATC.
Previous data from our lab have shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition often results in escape from growth arrest through mitotic slippage. This leads to the generation of polyploid, genetically unstable, cell populations.
We have tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines. Combined treatment with the PLK1 inhibitor BI6727 and the PI3K inhibitor BKM120 resulted in a significant synergistic effect in ATC cell lines with high levels of AKT activity, but not in those with undetectable pAKT. Combination of the two drugs enhanced the G2/M arrest at doses in which the single drugs showed no effect. In addition, it led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment with BI6727 and BKM120 in PI3Khigh cell lines showed a significant induction of apoptosis in a time- and dose-dependent manner.
Combined inhibition of PI3K and PLK1 was extremely effective in inhibiting tumor growth in vivo, in an immunocompetent allograft model of ATC.
Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with high levels of PI3K signaling. This combination results in cell cycle arrest, inhibition of of tetraploid cell generation, and induction of apoptosis, suggesting a clear therapeutic potential.
Citation Format: Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1068. doi:10.1158/1538-7445.AM2017-1068 |
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| ISSN: | 0008-5472 1538-7445 |