Abstract P6-10-19: Screening of GPCR-targeting drugs for repositioning in breast cancer

Abstract

Drug repositioning can overcome both substantial costs and the long process of new drug discovery and development in cancer treatment. Some FDA-approved drugs have been found to have the potential to be repositioned as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repositioning potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repositioning potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of anti-HER2 therapies. We identified 7 drugs/compounds as potential hits, out of which 4 were FDA-approved drugs. We focused on beta-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide (NO) production. Nebivolol reduced invasion and migration potentials which may suggest its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset found a reduced but not statistically significant risk of all-cause mortality in the nebivolol group. In-depth future analyses including detailed in vivo studies and real-world data analysis with more patients are needed to investigate further the potential of nebivolol as a repositioned therapy for BC. Citation Format: Noor Abdulkareem, Raksha Bhat, Reid Powell, Soumya Chikermane, Soham Yande, Lisa Trinh, Hala Abdelnasser, Alexis Ruiz, Mary Sobieski, Nghi Nguyen, Camille Johnson, Michael Johnson, Clifford Stephan, Meghana Trivedi. Screening of GPCR-targeting drugs for repositioning in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-19.