Abstract 3063: A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) is frequently diagnosed in younger women and is prevalent in African American women. Most TNBCs are highly aggressive with early pattern of metastasis, and with limited treatment options and poor prognosis. Finding effective therapeutic targets for TNBC has proven difficult so far. Therefore, there is an urgent need to develop new and novel therapeutic management of these patients. Recent studies have shown that glucocorticoid receptor (GR) is a mediator of pro-survival genes in TNBC cells, and its expression is predictive of increased risk of metastasis in TNBC tumors and decreased rate of patient survival. Therefore, blocking the effects of GR should be beneficial for TNBC patients. However, GR antagonists such as RU486 (mifepristone) targeting AF2/coactivators have shown only partial success in TNBC cell lines as well as in animal models. Based on our previous data we hypothesize that since in TNBC cells, the GR is constitutively active; therefore, attempts to block/inhibit GR activity through classic antagonists such as mifepristone that bind to ligand binding pocket of the receptor will have a limited clinical efficacy and higher side effects. To circumvent this problem, in this study, we propose a novel and innovative therapeutic approach to target constitutively active AF1 domain of the GR, which exists in an intrinsically disordered (ID) conformation. In this study, we tested our hypothesis that inhibiting/blocking TATA-box binding protein (TBP)-mediated GR’s AF1 activity by our newly identified molecule, PepT will attenuate TNBC cell survival via altering associated endogenous gene expressions. Our binding kinetics of AF1 showed that PepT binds to AF1 with about 10-fold higher affinity when compared with TBP’s binding to AF1. AF1 pre-bound with PepT fails to bind to TBP suggesting that PepT competes and blocks AF1-TBP interaction. We also found that treatment of MDA-MB-231 cells with PepT results in significant attenuation of cell viability and proliferation. Together, these results support our hypothesis that PepT has potential to kill TNBC cells by blocking GR AF1:co-regulator interactions. Citation Format: Shagufta H. Khan, Christian Carbe, Jun Ling, Raj Kumar. A novel mechanism for therapeutic targeting of the glucocorticoid receptor in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3063.