Despite intensive multimodal therapy, more than 50% of children with high-risk neuroblastoma eventually succumb to the disease. MYC signaling is a predominant driver of high-risk neuroblastoma, caused either by amplification of MYCN or by activation of cMYC. The bromodomain and extra-terminal (BET) domain-containing protein BRD4 was reported to cooperate with MYCN in the epigenetic regulation of super-enhancer driven genes in neuroblastoma. The BET inhibitors JQ1 and OTX015 were shown to repress BET/MYCN-mediated transcriptional control and antitumoral efficacy in MYCN-driven neuroblastoma. The potent BET inhibitor TEN-010, a derivative of JQ1, is currently in clinical trials for various MYC-driven adult tumors. Its efficacy against neuroblastoma is yet to be established.
In a preclinical setup, we investigated the antitumoral activity of TEN-010, OTX015 and JQ1 in neuroblastoma cell lines (n = 15) using ATP detection to assess cell viability 72h after treatment. To increase the therapeutic efficacy and decrease the risk of resistance formation, we subsequently turned towards combination therapies. We combined TEN-010 with conventional chemotherapeutics (e.g. etoposide) and with substances interfering with key pathways in neuroblastoma (e.g. volasertib).
Seven cell lines were highly sensitive to TEN-010 with IC50 values ranging 85nM to 632nM. Five cell lines showed an intermediate response (IC50: 1.5-4.8µM). Six of the seven highly sensitive lines displayed a decrease in viability by more than 75% at 1µM. Highest sensitivity was observed in cells with high MYCN/MYC activity, whereas TEN-010 showed a weaker effect in MYCN-non-amplified and low c-myc expressing cell lines. While OTX015 appears effective at lower concentrations, our data indicate a higher specificity, and thus potentially a larger therapeutic window, for TEN-010. First results of combinatorial approaches indicate synergistic effects lowering the IC50s into the low nanomolar range.
Our results support the notion that BET proteins have crucial functions in MYC/MYCN-driven neuroblastoma and suggest BET inhibition as an effective treatment option that may complement current standard therapy.
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German Cancer Consortium (DKTK), Innovative Medicines Initiative 2
All authors have declared no conflicts of interest.