title: Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications.
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.
authors.affiliation: Université de Bordeaux, Bordeaux, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), Institut Bergonié, Bordeaux, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fourneaux
authors.affiliation: Université de Bordeaux, Bordeaux, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), Institut Bergonié, Bordeaux, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chaire
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM), Institut Bergonié, Bordeaux, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Lucchesi
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Karanian
authors.affiliation: Université de Bordeaux, Bordeaux, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Pineau
authors.affiliation: Université de Bordeaux, Bordeaux, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), Institut Bergonié, Bordeaux, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche-Clary
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM), Institut Bergonié, Bordeaux, France.|Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D000068338:Everolimus / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011804:Quinolines; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C560077:trametinib; D000068338:Everolimus; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C531198:dactolisib
keywords: BEZ235; BKM120; PI3K/AKT/mTOR pathway; everolimus; leiomyosarcomas