GPCRs as novel potential therapeutic targets in cancer

Abstract

G protein‐coupled receptors (GPCRs) are the most widely targeted class of FDA‐approved therapeutics but in cancer, GPCRs are generally only targeted in endocrine tumors. We hypothesize that GPCRs have much broader importance in cancer and that therapeutics directed at GPCRs may have unappreciated utility in the treatment of a wide variety of cancers. To test this hypothesis, we have used unbiased approaches (Taqman GPCR arrays and RNA‐seq), mining of publicly available datasets (such as The Cancer Genome Atlas, TCGA), and validation studies to assess GPCRs in multiple human tumors, cancer cells and stromal cells (cancer‐associated fibroblasts, CAFs). A major focus has been on pancreatic ductal adenocarcinoma (PDAC) tumors and cells and pancreatic CAFs (PCAFs). We find that PDAC cells and PCAFs express >75 different GPCRs, including many orphan GPCRs (without known physiologic agonists) and that a substantial number of these GPCRs are expressed at much higher levels than in normal precursor cells. A cluster of GPCRs is overexpressed in PDAC tumors. Two of these receptors are orphan GPCRs (Orphan 1 and Orphan A), neither of which is mutated but each is highly expressed in PCAFs and PDAC cells, respectively. Both Orphan 1 and Orphan A have at least 2‐fold higher expression in >90% of PDAC tumors in TCGA compared to that of normal pancreas. Higher expression of orphan A is associated with increased mortality and a worse clinical course and Orphan 1 expression correlates with that of multiple fibrotic genes. Importantly, both Orphan 1 and Orphan A are functional and appear to contribute to the malignant phenotype. For example, siRNA knockdown of Orphan 1 in PCAFs blunts production of profibrotic markers and decreases ability of conditioned media from PCAFs to enhance proliferation of PDAC cells. Together, these and other results suggest that GPCRs represent previously unrecognized contributors to cancers besides endocrine tumors and as such, may be druggable, novel targets for the treatment of cancer, including pancreatic cancer, a tumor for which new therapeutics are a critical, unmet need.Support or Funding InformationNational Institutes of Health, National Cancer Institute (CA189477, CA121938, CA155620).