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 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 pre-malignant lesions and well-differentiated adenocarcinomas. Of note, SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG 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 mouse models 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.

Synthetic lethality targeting LKB1 mutant and EGFR wild type human non-small cell lung cancer cells by glucose starvation and SGLT2 inhibition

“…As mentioned above, the SGLT family proteins are involved in the active uptake of glucose, with predominant expression in intestine and kidney (Vrhovac et al, 2015). Moreover, it has been reported that functional SGLT2 expression is detected in various cancer types, including lung, pancreatic, prostate, colon, and liver cancers (Ishikawa et al, 2001;Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A).…”

“…Indeed, all 6 NSCLC cell lines expressed SGLT2 (Figure 6A). Targeting SGLT2 by its inhibitors has been shown to inhibit tumor cell growth in pancreatic, prostate, colon, liver and lung cancers (Kaji et al, 2018;Saito et al, 2015;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016). Thus, it is of interest and importance to investigating whether SGLT2 inhibitors would mimic the effect of glucose starvation in selective killing of the EGFR-WT/LKB1-mutant NSCLC cells.…”

“…Here we attempted to mimic glucose starvation both in vitro and in vivo by inhibition of glucose uptake and discovered that the SGLT2 inhibitor canagliflozin is highly effective in killing EGFR-WT/LKB1-mutant NSCLC cells. Although canagliflozin has been shown to inhibit tumor growth in multiple cancers including pancreatic, prostate, colon, liver and lung cancers (Kaji et al, 2018;Scafoglio et al, 2015;Scafoglio et al, 2018;Villani et al, 2016), this therapeutic agent has not been studied as a target therapy. In this study, we tested the efficacy of canagliflozin on inhibiting tumor growth both in vitro and in vivo.…”

“…Based on this, SGLT2 inhibitors, named gliflozins, have been successfully developed as the first line anti-diabetic drugs, including canagliflozin, dapagliflozin, and empagliflozin (Haas et al, 2014). Recently, SGLT2 has been shown as a diagnostic and therapeutic target for early-stage lung adenocarcinoma, and SGLT2 inhibitors greatly reduced lung tumor growth (Scafoglio et al, 2018). At this stage, it is not known whether the therapeutic effects of SGLT2 inhibitors are associated with the LKB1-AMPK pathway.…”

Is cancer incidence modified by SGLT2 inhibitors?

“…В частности, предложен специфический для SGLT2 зонд для позитронно-эмиссионной томографии (α-methyl-4-[F-18] fluoro-4-deoxy-d-glucopyaranoside, или Me-4FDG), который может быть использован для анализа натрий-зависимых котранспортеров глюкозы в опухолевой ткани, связи опухолевого роста с углеводным обменом [22,23] и последствий соответствующих применений глифлозинов. В том числе, речь может идти о том, чтобы использовать SGLT2 как мишень для лечения злокачественных новообразований [24], имея в виду онкологических больных как страдающих, так и не страдающих диабетом, а ингибиторы SGLT2 -как средство воздействия и на опухолевую ткань. В целях проверки было показано, что при оценке экспрессии SGLT2 метаболическая активность опухолевой ткани (по захвату глюкозы) на примере бронхокарциномы была наиболее высока на ранних ее этапах, когда процесс характеризуется высокой степенью дифференцировки.…”