Potential Applications of BET Inhibitors in Combination with other Anti-Cancer Agents

Bromodomain and Extra-Terminal Domain (BET) proteins are a family of epigenetic readers which bind to specific acetylated lysine residues located on histone tails. These proteins are involved in the regulation of a number of essential biological functions, consequently aberrations of these proteins and dysregulation of the pathways they regulate is associated with oncogenesis. A number of studies have provided proof of concept that inhibition of BET proteins could be a viable therapeutic strategy for the treatment of cancer.

A qualitative systematic literary review was conducted, with a focus on the development of resistance to BET inhibitors in cancer, as well as the use of BET inhibitors to aid overcoming drug resistance to other classes of chemotherapeutics. The review identified several factors responsible for the acquisition of resistance to BET inhibitors which might aid in determining effective combination therapies and guide the development of next-generation BET inhibitors. Furthermore, the review showed evidence of BET inhibitors conferring a synergistic effect in resistant cancer cell lines when used in combination with other chemotherapeutic agents, in some instances assisting in overcoming drug resistance by increasing the sensitivity of cancer cell lines to other anti-cancer agents.

Cell viability of the neuroblastoma cell lines following treatment with the platinum-based drugs, carboplatin and oxaliplatin, and the BET inhibitors, JQ1 and I-BET726, as single agents was assessed. Each of the cell lines demonstrated increased sensitivity to I-BET726 compared to JQ1, with this effect most apparent in the oxaliplatin-resistant neuroblastoma cell line. Furthermore, the responses to JQ1 demonstrated greater variation than the responses to I-BET726.

Moreover, this study investigated the impact of the structurally different BET inhibitors on the sensitivity of the neuroblastoma cell line, UKF-NB-3, and its carboplatin- (UKF-NB-3rCARBO2000) and oxaliplatin-resistant (UKF-NB-3rOXALI2000) sublines to carboplatin and oxaliplatin respectively. Pre-treatment with the BET inhibitors increased the sensitivity of the cell lines to their respective platinum compound, with the response to the platinum agents improving as the pre-treatment concentration and duration increased.

The findings from the literary review highlights the potential of BET inhibitors to aid in overcoming resistance when used in combination with other classes of chemotherapeutics. This finding is corroborated by the results generated within the wet lab portion of this study which demonstrate this in neuroblastoma against platinum-based drugs.