The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

// Nabil Amirouchene-Angelozzi 1, 6 , Estelle Frisch-Dit-Leitz 1 , Guillaume Carita 2 , Ahmed Dahmani 2 , Chloe Raymondie 2 , Geraldine Liot 3 , David Gentien 4 , Fariba Nemati 2 , Didier Decaudin 2, 5 , Sergio Roman-Roman 1, * , Marie Schoumacher 1, * 1 Translational Research Department, Institut Curie, PSL Research University, Paris, France 2 Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France 3 Unite Mixte de Recherche 3347, Institut Curie, PSL Research University, Orsay, France 4 Genomics Platform, Translational Research Department, Institut Curie, PSL Research University, Paris, France 5 Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France 6 Current address: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy * These authors contributed equally to this work Correspondence to: Sergio Roman-Roman, email: sergio.roman-roman@curie.fr Keywords: uveal melanoma, preclinical models, PI3K, mTOR, apoptosis Received: October 06, 2015      Accepted: February 29, 2016      Published: March 14, 2016 ABSTRACT Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients.