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

Ahmed M Elshazly; Melanie M Sinanian; Victoria Neely; Eesha Chakraborty; Muruj A Alshehri; Michael K McGrath; Hisashi Harada; Patricia V Schoenlein; David A Gewirtz

doi:10.3390/cancers15164066

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

Cancers (Basel). 2023 Aug 11;15(16):4066. doi: 10.3390/cancers15164066.

Authors

Ahmed M Elshazly^{1

2

3}, Melanie M Sinanian^{1

2}, Victoria Neely^{2

4}, Eesha Chakraborty^{2

5}, Muruj A Alshehri^{1

2

6}, Michael K McGrath⁷, Hisashi Harada^{2

4}, Patricia V Schoenlein⁷, David A Gewirtz^{1

2}

Affiliations

¹ Departments of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
² Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
³ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
⁴ Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁵ C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁶ Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
⁷ Department of Cellular Biology and Anatomy, MCG Cancer Center, Augusta University, Augusta, GA 30912, USA.

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.

Keywords: ABBV-744; ARV-825; BRD4; c-Myc; p53; senescence.

Grants and funding

Research in the Gewirtz laboratory is supported by grants # CA268819 and CA239706 from the National Cancer Institute/National Institutes of Health and Grant # W81XWH 19-1-0490 from the Department of Defense Congressionally Directed Breast Cancer Research Program. Shared resources such as the Flow Cytometry laboratory that provided assistance to this project were supported by funding from Massey’s NIH-NCI Cancer Center Support grant P30 CA016059.