GPCRs in Oncology

G protein-coupled receptors (GPCRs) are the largest family of receptors that reside on the surface of human cells. These complex receptors mediate many important physiological functions by binding to extracellular ligands and differentially controlling many signaling pathways inside cells. Due to the diversity of this receptor family and their control of a large number of signaling pathways, GPCRs are commonly dysregulated in human diseases, and more than a third of all marketed drugs engage one or more of these receptors. As a result, GPCRs represent one of the largest families of proteins that have been safely and successfully targeted in modern medicine.

Surprisingly few GPCR-targeted therapies have been developed for oncology, despite frequent dysregulation of the receptors and their signaling mediators that control pro-survival and stress signaling pathways that are important in cancer. Furthermore, the clinically validated ability to target GPCRs safely without cytotoxic effects to normal cells represents a significant opportunity for novel therapeutics that contrast with currently available chemotherapies and targeted agents. Imipridones, the chemical class developed by Oncoceutics, are a novel class of anti-cancer compounds that selectively target GPCRs. The first imipridone to enter the clinic is ONC201, which specifically antagonizes the GPCR DRD2. This makes ONC201 the first clinical molecule for oncology that targets a neurotransmitter pathway and raises a few key  questions.

At an event hosted by Oncoceutics, Dr. Joshua Allen of Oncoceutics, and Dr. Paul Insel and Dr. Silvio Gutkind of UC San Diego discussed the role that GPCRs play in cancer, and the potential of GPCR targeting agents in oncology.

Does it make sense that a GPCR that controls neurotransmitter pathways plays an important role in oncology?

DRD2 is overexpressed by several types of human cancer and its inhibition is associated with anti-cancer activity. This is documented by studies describing: 1) elevated DRD2 expression in malignant cells compared with normal cells; 2) preclinical studies documenting the antitumor effects of antagonizing DRD2 signaling; and 3) observed associations of cancer incidence with other diseases that affect dopamine receptor signaling. This is consistent with finding that DRD2 impacts several signaling cascades that are intimately involved in cancer cell survival, angiogenesis, migration, and metastasis.

First, there is a large body of literature indicating elevated DRD2 expression in malignant cells compared with normal cells in several tumor types. Moreover, this overexpression tends to increase with the stage of the disease. See here for studies indicating elevated DRD2 expression in malignant cells compared with normal cells.

Second, there are a large number of preclinical studies documenting the antitumor effects of antagonizing DRD2 signaling, either through genetic or pharmacological inhibition (here). The most widely reported investigations of DRD2 inhibition in preclinical models in oncology is with thioridazine, an antipsychotic DRD2 antagonist that is pro-apoptotic, anti-angiogenic, and depletes cancer stem cells in preclinical models of several tumor types. Several pro-survival and stress signaling pathways have been implicated in the antitumor mechanism of DRD2 inhibitors, including downregulation of Ras signaling and upregulation of oxidative stress.

Third, there are meta-analyses that have examined cancer incidence in populations with dysregulated dopamine receptor signaling and have found that dopamine blockade leads to lower levels of cancer. For example, a meta-analysis of patients with Parkinson’s disease, where dopamine is downregulated (effectively antagonizing dopamine receptors), revealed a significantly reduced incidence of most cancers.  Interestingly, while this association was true for most solid and hematological malignancies, the exceptions – including melanoma and thyroid cancers – are tumors with low expression of DRD2. A similar analysis of schizophrenic patients where dopamine is upregulated, found an increase in cancer incidence that is reversed in patients who are compliant with treatments that antagonize dopamine.

How does a dopamine receptor impact signaling pathways involved in cancer?

DRD2 is a member of the dopamine receptor family that is grouped into two classes: the D1-like receptor class composed of DRD1 and DRD5 and the D2-like receptor class composed of DRD2 (with the highest affinity for dopamine), DRD3, and DRD4. All of the dopamine receptors are GPCRs, whose signaling is primarily mediated by interaction with and activation of heterotrimeric GTP-binding proteins (G proteins). GPCRs control pro-survival signaling pathways (e.g. ERK and Akt) that are broadly important in human cancer.

The D2-like receptor family is coupled to specific types of G proteins that mediate their signaling. One type of G protein coupled to D2-like receptor activation acts as an inhibitor of adenylate cyclase, a key enzyme involved in the synthesis of cyclic AMP (cAMP) that affects many intracellular signaling pathways. By contrast, the D1-like family of receptors is coupled to a different type of G protein that stimulates adenylate cyclase and thus opposes D2-like receptor signaling.

Activation of D2-like receptors also stimulates ERK and Akt signaling that promotes cancer cell survival. The mechanism that couples D2-like receptors to this signaling is complex and differs depending on cell type, but often involves scaffold proteins such as KSR-1 or β-arrestin that are recruited to the activated GPCR and facilitate kinase signaling cascades.

Click here for scientific literature on GPCRs in oncology.