2023 World Conference on Lung Cancer (Posters)-P1.02. Glucose Deprivation Promotes Pseudo-Hypoxia and De-differentiation in Lung Adenocarcinoma

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This session at the WCLC 2023 conference presented research on lung adenocarcinoma (LUAD) and its relationship with glucose metabolism. The study identified sodium-glucose transporter 2 (SGLT2) as a critical player in glucose uptake in pre-malignant and well-differentiated LUAD cells, while advanced and poorly differentiated tumors relied on GLUT1 for sugar uptake. SGLT2 inhibitors (SGLT2i), which are already FDA-approved for diabetes and other conditions, were found to delay LUAD development and extend survival in mouse models. However, resistance to SGLT2i treatment was observed in the mice that still developed tumors. <br /><br />The researchers conducted treatment trials using the SGLT2i empagliflozin in genetically engineered mouse models of LUAD. Glucose deprivation was found to block tumor proliferation but also induced de-differentiation and a more aggressive phenotype in the long term. Glucose restriction led to a reduction in alpha-ketoglutarate (αKG), resulting in decreased activity of αKG-dependent histone demethylases and increased histone hypermethylation by EZH2. The de-differentiated phenotype was dependent on unbalanced EZH2 activity, and combining SGLT2i empagliflozin with EZH2 inhibitor tazemetostat had an additive effect in attenuating starvation-induced de-differentiation.<br /><br />Further investigation revealed that increased EZH2 activity inhibited prolyl-hydroxylase PHD3 and upregulated hypoxia-inducible factor 1α (HIF1α), leading to epithelial-to-mesenchymal transition. Additionally, an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD was identified.<br /><br />The study concluded that glucose deprivation, whether induced by SGLT2 inhibition or low glucose incubation, had a dual effect on LUAD. On one hand, it reduced proliferation by limiting glycolytic intermediates needed for cell growth. On the other hand, it promoted de-differentiation and transition to a more aggressive phenotype through starvation-induced de-differentiation. Combining EZH2 inhibitors with SGLT2i could potentially prevent de-differentiation. This research improves our understanding of the relationship between glucose metabolism and cell differentiation in cancer and identifies new targets for preventing therapy resistance related to glucose metabolism in LUAD.

Asset Subtitle

Claudio Scafoglio

Meta Tag

Speaker Claudio Scafoglio

Topic Tumor Biology: Preclinical Biology - Molecular Therapeutic Targets

Keywords

lung adenocarcinoma

glucose metabolism

sodium-glucose transporter 2

SGLT2

GLUT1

SGLT2 inhibitors

empagliflozin

EZH2 inhibitor

prolyl-hydroxylase PHD3

hypoxia-inducible factor 1α