BRD4 Inhibition as a Strategy to Prolong the Response to Standard of Care in Estrogen Receptor-Positive Breast Cancer

SIMPLE SUMMARY: The combination of CDK4/6 inhibitors + fulvestrant or tamoxifen effectively prolongs survival in patients with estrogen receptor-positive (ER(+)) breast cancer. However, in the case of residual and metastatic disease, morbidity and mortality are virtually inevitable. Recently, the targeting of dysregulated epigenetic elements, and particularly BET family proteins, has generated considerable interest in the cancer field. The current study was designed to evaluate the capacity of BET inhibitors ARV-825 and ABBV-744 to improve the response to standard-of-care treatment in ER(+) breast cancer. ARV-825 was effective when combined with tamoxifen in both p53 wild type and p53 null ER(+) breast cancer cell lines while ABBV-744 showed effectiveness only in combination with fulvestrant plus palbociclib in p53 wild-type cells. Downregulation of both BRD4 and c-Myc are implicated as being required for the sensitizing effects of ARV-825 while c-Myc may not be involved in the case of ABBV-744. ABSTRACT: Breast cancer is the most commonly occurring malignancy in women and the second most common cause of cancer-related deaths. ER(+) breast cancer constitutes approximately 70% of all breast cancer cases. The standard of care for ER(+) breast cancer involves estrogen antagonists such as tamoxifen or fulvestrant in combination with CDK4/6 inhibitors such as palbociclib. However, these treatments are often not curative, with disease recurrence and metastasis being responsible for patient mortality. Overexpression of the epigenetic regulator, BRD4, has been shown to be a negative prognostic indicator in breast cancer, and BET family inhibitors such as ARV-825 and ABBV-744 have garnered interest for their potential to improve and prolong the response to current therapeutic strategies. The current work examined the potential of utilizing ARV-825 and ABBV-744 to increase the effectiveness of tamoxifen or fulvestrant plus palbociclib. ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4.