Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy

Purpose: TERT gene rearrangement with transcriptional super-enhancers leads to TERT over-expression and neuroblastoma. No targeted therapy is available for clinical trials in TERT-rearranged neuroblastoma patients.

Experimental design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening a US Food and Drug Administration-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice.

Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through up-regulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT over-expression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression and improved mouse survival, which was largely reversed by forced TERT over-expression.

Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in TERT-rearranged neuroblastoma patients.

Related Products

Cat.No.	Product Name	Information
S7360	Birabresib (OTX015)	Birabresib (OTX015, MK 8628) is a potent BET bromodomain inhibitor with EC50 ranging from 10 to 19 nM for BRD2, BRD3, and BRD4 in cell-free assays. Birabresib inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes.

Related Targets

Epigenetic Reader Domain