Open AccessTargeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma
Author(s) -
Michael K. Kießling,
Alessandra Curioni-Fontecedro,
Panagiotis Samaras,
Silvia Lang,
Michael Scharl,
Adriano Aguzzi,
Derek A. Oldrige,
John M. Maris,
Gerhard Rogler
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0147682
Subject(s) - everolimus , neuroblastoma ras viral oncogene homolog , pi3k/akt/mtor pathway , neuroblastoma , cancer research , cell growth , protein kinase b , mek inhibitor , biology , cell culture , mapk/erk pathway , apoptosis , medicine , cancer , oncology , microbiology and biotechnology , signal transduction , biochemistry , kras , genetics , colorectal cancer
High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies.