Abstract 2713: Combination of PLK1 and PI3K inhibitors shows strong synergy in anaplastic thyroid cancer

Abstract

Abstract Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer with median of 6 months of survival from diagnosis. Molecular alterations are well defined recently. p53 mutations, and activation of PI3K, RAS and BRAF are among the most common alterations. PLK1 overexpression has also been identified in ATC. We have previously shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition in cell lines with PI3K activation resulted in escaping growth arrest and subsequent mitotic catastrophe through mitotic slippage. Since the PI3K activation is common in ATC, there is risk of generating polyploid, genetically unstable cell populations by targeting these tumors with a PLK1 inhibitor. So we tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines. We combined PLK1 inhibitor BI6727 and PI3K inhibitor BKM120 and measured the cell viability using Alamar Blue. Combination of these two drugs resulted in significant synergy in mouse derived PTEN deleted ATC cell lines. We observed the same synergy in the human ATC cell lines with PIK3CA mutations. BI6727 showed significant G2/M arrest in the cell lines. The combination two drugs enhanced the G2/M arrest. In a low dose that the single drugs showed no inhibition in cell cycle, combination resulted in G2/M arrest. We treated the cells with a dual PI3K and PLK1 inhibitor Rigosertib. Although we have seen some sensitivity of the cells with PIK3CA mutation, the cell lines with PTEN were strongly resistant to Rigosertib. Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with PI3K activation. This combination results in cell cycle arrest suggesting the role of using combination therapies in this aggressive cancer. Citation Format: Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Combination of PLK1 and PI3K inhibitors shows strong synergy in anaplastic thyroid cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2713.