Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma

Abstract

The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions andwell-differentiated adenocarcinomas. SGLT2 activity could be detected in vivoby positron emissiontomography (PET)with the tracer methyl 4-deoxy-4-[18F] fluoro-alpha-D-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry andMe4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mousemodels and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors.