P2.03-21 Mechanistic Investigation of DRD1 in Lung Cancer

The D1 dopamine receptor (DRD1) is a G protein-coupled receptor (GPCR) for the catecholamine dopamine (DA). Historically, DA was thought to function mainly within the central nervous system (CNS), and there have been no prior reports linking the DA pathway (DAP) to lung cancer biology. Our group previously discovered an epidemiological association between a DRD1 gene polymorphism and risk of developing lung cancer. Since this association was observed in never smokers,it suggested that DRD1 may play a direct role in the pathogenesis of lung cancer. We have been investigating this novel function of DRD1. The DAP has never been fully characterized in lung. We therefore examined the presence of DAP-related proteins, including dopamine receptors, metabolizing and synthesizing enzymes, and dopamine transporter in normal human lung tissue. To understand the mechanistic role of DRD1 in lung cancer, we generated stable lung cancer cell lines in which DRD1 was overexpressed or knocked down and performed proliferation, transcriptome, and kinome analysis. We found that dopamine-related proteins are expressed throughout the respiratory tract in normal human tissue. Further, we observed that DRD1 expression is significantly downregulated in lung cancer using samples from the on NCI-MD case control study and replicated this with TCGA. Methylation analyses in NCI-MD and TCGA showed that DRD1 is hyper-methylated in lung cancer and that there is a negative correlation between DRD1 mRNA and methylation. DRD1 methylation and methylation are associated with patient outcome. Modulation of DRD1 in multiple cell line model systems affects cell proliferation. Transcriptome and kinome profiling revealed that this modulation is mediated through EGFR and downstream MAPK and AKT signaling. Immunofluorescent staining shows that EGFR and DRD1 colocalize at the cell membrane. Ongoing work is aimed at establishing the exact nature of the DRD1/EGR interaction. Collectively, this work suggests that DRD1 acts like a tumor suppressor in lung cancer, that inherited susceptibility in the DRD1 gene contributes to lung cancer and agents that modulate the bioavailability of dopamine could modulate patient survival. Understanding the possible crosstalk between DRD1, EGFR and MAPK signaling may be very valuable for lung cancer therapeutic strategy. The majority of patients receiving EGFR inhibitors eventually develop resistance. Using DRD1 agonists as combinatorial agents may help bypassing anti-EGFR resistance.