The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma
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Nabil Amirouchene-Angelozzi1,6, Estelle Frisch-Dit-Leitz1, Guillaume Carita2, Ahmed Dahmani2, Chloé Raymondie2, Géraldine Liot3, David Gentien4, Fariba Némati2, Didier Decaudin2,5, Sergio Roman-Roman1,*, Marie Schoumacher1,*
1Translational Research Department, Institut Curie, PSL Research University, Paris, France
2Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France
3Unité Mixte de Recherche 3347, Institut Curie, PSL Research University, Orsay, France
4Genomics Platform, Translational Research Department, Institut Curie, PSL Research University, Paris, France
5Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France
6Current address: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy
*These authors contributed equally to this work
Sergio Roman-Roman, email: firstname.lastname@example.org
Keywords: uveal melanoma, preclinical models, PI3K, mTOR, apoptosis
Received: October 06, 2015 Accepted: February 29, 2016 Published: March 14, 2016
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.
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