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DOI: 10.1055/s-0038-1645001
Preclinical evaluation of BET-inhibition as monotherapy and combination therapy in MYC-driven neuroblastoma
Publication History
Publication Date:
08 May 2018 (online)
Introduction:
MYC signaling is a predominant driver of high-risk neuroblastoma (NB), caused either by amplification of MYCN or by activation of cMYC. The BET protein BRD4 was shown to cooperate with MYCN in the epigenetic regulation of super-enhancer driven genes in NB. The BET inhibitors OTX015 and JQ1 demonstrated anti-neuroblastoma efficacy. TEN-010 is currently in clinical trials for adult tumors, but its efficacy against NB is yet unknown.
Methods:
72h after treatment with TEN-010, OTX015 or JQ1, we assessed cell viability in NB cell lines using ATP detection. Subsequently, we tested combinations of TEN-010 with conventional chemotherapeutics (e.g. etoposide) and substances interfering with other key pathways (e.g. volasertib).
Results:
Our data indicate a higher specificity for TEN-010, and thus potentially larger therapeutic window. Sensitivity positively correlated with the MYCN/MYC activity score. First results of combinatorial approaches indicate synergistic effects.
Conclusion:
Our results suggest BET inhibition and combination therapies as an effective treatment option that may complement current standard therapy in MYC-driven NB.