Screening of GPCR drugs for repurposing in breast cancer

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 β-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 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.

Molecular characterization of breast cancer cell pools with normal or reduced ability to respond to progesterone: a study based on RNA-seq

“…We considered that seven of them may be of special interest as they have been described before in the context of breast cancer [ 48 , 52 – 60 ]; they all are affected by P4 and relate to G protein-coupled receptor (GPCR) signaling pathways. GPCR-mediated signaling has been implicated in growth regulation, tumor initiation, tumor progression, invasiveness, and metastasis [ 52 , 57 , 61 – 67 ].…”

The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer

“…From the prevalence of GPCRs in current drug design and the role they play in cancer, it is not surprising that the development of cancer drugs that target GPCRs is gaining traction [141,[147][148][149]. A variety of different treatment strategies are under development, including small molecule pharmacological compounds that target GPCRs and G proteins [150], as well as antibody-based approaches [84].…”

Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures

“…In the quest for potential novel targets and drugs to prevent tumor progression and metastasis, drug repurposing is of increasing interest. Thus, ß-blockers have advantages over new drugs as they have already undergone the time-consuming and costly process of the Food and Drug Administration (FDA) approval and thus represent an immediately available option, with the common contraindications and side effects already identified [ 9 , 10 , 11 ].…”

“…It depicts the highest selectivity for β1-receptors and has an additional vasodilatory effect mediated by interacting with the L-arginine/nitric oxide pathway via β3-receptor agonism, which may also lead to a reduction of oxidative stress [ 14 , 17 , 21 , 22 ]. A tumor inhibitory effect of nebivolol has recently been described in tumors such as breast, lung, and oral squamous cell cancer [ 11 , 23 , 24 ]. However, studies on the effect of β1-selective blockers, such as nebivolol, in ocular cancers are still lacking.…”