Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications.

Benjamin Fourneaux,Antoine Italiano,Marie Karanian,Carlo Lucchesi,Vanessa Chaire,Audrey Laroche-Clary,Raphael Pineau

doi:10.18632/oncotarget.13987

Benjamin Fourneaux, Antoine Italiano + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.13987

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Journal: Oncotarget	Publication Date: Dec 16, 2016
Citations: 18	License type: cc-by

Affiliation: University of Bordeaux, Institut Bergonié, Inserm

Abstract

The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS.

Highlights

Leiomyosarcomas (LMSs) are an uncommon group of malignant tumors composed of cells that show distinct smooth muscle differentiation and that represent 15–20% of all soft-tissue sarcomas, making LMS one of the most frequent sarcoma subtypes [1]
Exposure to high doses of BEZ235 and BKM120 led to induction of apoptosis as revealed by 40% and 65% increases in the percentage of annexin V- and propidium iodide (PI)-positive cells compared to control cells (Figure 3A and 3B)
We report an original study assessing the respective in vitro and in vivo effects of a drug panel targeting different components of the PI3K/AKT/mTOR pathway on human leiomyosarcoma, an extremely rare form of cancer

Summary

Introduction

Leiomyosarcomas (LMSs) are an uncommon group of malignant tumors composed of cells that show distinct smooth muscle differentiation and that represent 15–20% of all soft-tissue sarcomas, making LMS one of the most frequent sarcoma subtypes [1]. In vitro and in vivo studies have highlighted the critical role of the PI3K/mTOR pathway in smooth muscle transformation and LMS development [10] In these studies, mTOR inhibition was associated with significant anti-tumor activity [11]. Several studies have shown that inhibition of mTOR by rapamycin and its analogs is associated with a loss of negative feedback control of the MAPK pathway [14] and PI3K/AKT/mTOR pathway in solid tumors [15, 16] This finding may explain the transient benefit observed with mTOR inhibitors in a clinical setting and the need for more potent strategies to target this pathway [17]

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