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 1, 2 , Vanessa Chaire 1, 2 , Carlo Lucchesi 2 , Marie Karanian 3 , Raphael Pineau 1 , Audrey Laroche-Clary 1, 2 , Antoine Italiano 2, 3 1 Universite de Bordeaux, Bordeaux, France 2 Institut National de la Sante et de la Recherche Medicale (INSERM), Institut Bergonie, Bordeaux, France 3 Department of Medical Oncology, Institut Bergonie, Bordeaux, France Correspondence to: Antoine Italiano, email: A.Italiano@bordeaux.unicancer.fr Keywords: leiomyosarcomas, PI3K/AKT/mTOR pathway, BEZ235, BKM120, everolimus Received: September 14, 2016 Accepted: December 05, 2016 Published: December 16, 2016 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.