BRD4-targeting PROTACs Synergize With Chemotherapeutics Against Osteosarcoma Cell Lines

Osteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles. This work aimed to investigate the efficacy of BETi, such as JQ1, dBET57, and MZ1 PROTACs in combination with cytotoxic drugs against osteosarcoma cell lines.

Chemosensitivity of the osteosarcoma cell lines HOS, Saos-2, MG-63, and G292 were tested with BET-directed agents alone or in combination with cytotoxic drugs comprising cisplatin, doxorubicin, topotecan, and gemcitabine using cell viability assays.

The BET degraders exhibited highest toxicity to HOS cells and showed synergistic activity in combination with the chemotherapeutics, except for the degrader - topotecan/gemcitabine combinations. Highest synergy between BET agents and chemotherapeutics were found for the more chemoresistant Saos-2 cells and potentiation of toxicity in MG-63 cells for the BET agents - doxorubicin combinations and the MZ1-topotecan pair. HOS and Saos-2 cell lines had reduced protein expression of AXL, BCL-X, e-cadherin, CAIX, EpCAM, ErbB2, and vimentin in response to JQ1, MZ1, and BET57.

The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials.