Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype

Abstract

G protein-coupled receptors (GPCRs) are the most common class of therapeutic targets, accounting for ~35% of all FDA-approved drugs. Cancer patients receive numerous medications not only to combat cancer but also to alleviate pain, nausea, and anxiety, many of which target GPCRs. Emerging evidence has implicated GPCRs as drivers of cancer progression, therapeutic resistance, and metastasis. Therefore, the effects of commonly prescribed GPCR-targeted drugs must be reevaluated in the context of cancer. Epidemiological and experimental evidence indicate that widely used GPCR-targeted drugs may promote or inhibit cancer progression. It is crucial that we more fully understand the indirect effects of GPCR-targeted drugs on the cancer phenotype. This review summarizes recent advances in characterizing these interactions and highlights future research opportunities.

Keywords: G protein-coupled receptor; GPCR; GPCR drugs; cancer; drug targets.

Figure 1. Key Figure. GPCR-Targeted Drugs Indirectly Modulate the Cancer Phenotype

Many drug classes target GPCRs. This review addresses cardiac, antiemetic, anti-inflammatory, analgesic, antidiabetic, parasympathetic, and neuropsychiatric drugs that either promote or inhibit GPCR signaling, and subsequently influence aspects of the cancer phenotype, including angiogenesis, immunity, cell proliferation, metastasis, and tumor–stroma crosstalk. Abbreviation: GPCR, G protein-coupled receptor.

Figure I.. Drug–Receptor Activity Terms.

GPCR-targeted drugs can modulate GPCR signaling by activating the canonical signaling pathway (agonists, partial agonists) or alternative downstream signaling pathways (biased agonists). Antagonists and inverse agonists inhibit GPCR signaling. Abbreviation: GPCR, G protein-coupled receptor.

Figure II.. GPCR Signaling.

GPCR signaling occurs when a ligand binds to the receptor and produces a conformational change that either activates or inhibits the activity of heterotrimeric G proteins. G proteins then regulate specific downstream signaling pathways depending on the type of G_α subunit linked to a GPCR. Abbreviation: GPCR, G protein-coupled receptor.

Figure I.. PubMed Search Query Results for Each GPCR and Cancer from 1977 to 2020.

Some GPCRs have been heavily researched in the context of cancer, whereas the role of others is newly established. Abbreviation: GPCR, G protein-coupled receptor.