Open AccessThe mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma
Author(s) -
Nabil Amirouchene-Angelozzi,
Estelle Frisch-Dit-Leitz,
Guillaume Carita,
Ahmed Dahmani,
Chloé Raymondie,
Géraldine Liot,
David Gentien,
Fariba Némati,
Didier Decaudin,
Sergio Roman-Roman,
Marie Schoumacher
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.8054
Subject(s) - pi3k/akt/mtor pathway , everolimus , medicine , discovery and development of mtor inhibitors , protein kinase b , melanoma , cancer research , mek inhibitor , mapk/erk pathway , apoptosis , pharmacology , oncology , kinase , biology , biochemistry , microbiology and biotechnology
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.