Abstract B095: Targeted inhibition of SLC2A5 prevents tumour growth and metastasis

Abstract

Endoplasmic reticulum (ER) stress plays an integral part during cancer progression and is utilized as an adaptive mechanism in stressful environments. During tumour formation, cancer cells experience a hostile microenvironment composed of a lack of oxygen, nutrients and lipids and an acidic pH and they undergo high metabolic demands, with increased protein production and cellular growth. Using an ER Stress reporter assay we discovered that silencing the fructose transporter SLC2A5 (GLUT5) gene and, consequently, reduced uptake of fructose resulted in inhibition of the IRE1α/spXBP1 arm of the ER stress response. The loss of the fructose transporter inhibits cancer cell migration and proliferation in MIA-PaCa-2 pancreatic cancer cells (Groenendyk, et al. 2022). RPPA analysis of SLC2A5-deficient pancreatic cancer cells identified STAT3 playing an essential role in the response to reduced fructose uptake. STAT3 association with the mitochondria was reduced in the absence of the fructose transporter. Membrane contact SPLICS analysis revealed the loss of the close mitochondrial-ER contacts in SLC2A5-deficient MIA-PaCa-2 cells. Reduced Ca2+ transfer to mitochondria in SLC2A5-deficient MIA-PaCa-2 cells was accompanied by increased amount of reactive oxygen species (ROS) and impaired energy metabolism. We identified two derivatives of a known GLUT5 inhibitor that prevent fructose transport in the micromolar to nanomolar range using in-silico molecular docking, followed by chemical synthesis, in vitro cytotoxicity, proliferation and adhesion analysis and in vivo tumour xenograft experiments to determine the mechanism dictating essential fructose functions in cancer. We identified novel compounds that are promising drug candidates for combination therapy with effective chemotherapy, providing more time for chemotherapy efficaciousness and less worry about metastasis. Jody Groenendyk, Kamlesh Sahu, Lorne D. Tyrell, Michael Houghton, Marek Michalak. Targeted inhibition of SLC2A5 prevents tumour growth and metastasis [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B095.