The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus

Abstract
Triple-negative breast cancer (TNBC) is a particularly aggressive and diverse type of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors. This makes targeted therapies used for other types of breast cancer less effective. Recent research highlights c-MYC as a crucial driver of TNBC. The BET-bromodomain inhibitor OTX015 (MK-8628) has shown strong anti-proliferative effects and reduces c-MYC levels in various tumors. It also exhibits synergistic effects when combined with the mTOR inhibitor everolimus in different models.

This study aimed to assess the effectiveness of OTX015 alone and in combination with everolimus in TNBC models. OTX015 was tested on three human TNBC cell lines—HCC1937, MDA-MB-231, and MDA-MB-468. After 72 hours of treatment, OTX015 displayed anti-proliferative activity (GI50 = 75-650 nM) in all three cell lines, leading to cell cycle arrest and reduced expression of cancer stem cell markers. Notably, c-MYC protein and mRNA levels were only decreased in MDA-MB-468 cells. Gene set enrichment analysis revealed an up-regulation of genes related to epigenetic transcription control, chromatin dynamics, and the cell cycle, alongside a down-regulation of stemness-related genes.

When combined with everolimus, the effects were additive in HCC1937 and MDA-MB-231 cells, but antagonistic in MDA-MB-468 cells. In murine xenograft models using MDA-MB-231 cells, OTX015 significantly reduced tumor mass compared to vehicle-treated controls (best T/C = 40.7%, p < 0.05). Although everolimus alone showed no activity, the combination with OTX015 proved more effective (best T/C = 20.7%). These findings support ongoing clinical trials evaluating OTX015 in OTX015 TNBC (NCT02259114).