Screening of GPCR drugs for repurposing in breast cancer. Academic Article uri icon

abstract

  • Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing 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 HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on -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 3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced 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 further investigate the potential of nebivolol as a repurposed therapy for BC.

published proceedings

  • Front Pharmacol

altmetric score

  • 4.35

author list (cited authors)

  • Abdulkareem, N. M., Bhat, R., Powell, R. T., Chikermane, S., Yande, S., Trinh, L., ... Trivedi, M. V.

citation count

  • 1

complete list of authors

  • Abdulkareem, Noor Mazin||Bhat, Raksha||Powell, Reid T||Chikermane, Soumya||Yande, Soham||Trinh, Lisa||Abdelnasser, Hala Y||Tabassum, Mantasha||Ruiz, Alexis||Sobieski, Mary||Nguyen, Nghi D||Park, Jun Hyoung||Johnson, Camille A||Kaipparettu, Benny A||Bond, Richard A||Johnson, Michael||Stephan, Clifford||Trivedi, Meghana V

publication date

  • January 2022