Abstract 6793: Characterizing glucose transport at incremental stages of chemoresistance in melanoma

Abstract Multidrug resistance (MDR) presents major challenges in cancer treatment as cancer cells evolve to evade the effects of chemotherapy. This resistance is driven by various cellular mechanisms, including the overproduction of transport proteins that regulate the intake of essential nutrients and the removal of xenobiotics. While the mechanisms underlying drug efflux in MDR cancers are well studied, the role of carbohydrate transport proteins, like glucose transporters (GLUTs), remains poorly characterized as cells become increasingly resistant to chemotherapy. As interest grows in using glycoconjugation for targeted drug delivery, understanding how sugar transport and metabolism are altered in MDR cancers could be crucial for enhancing the specificity and efficiency of these strategies. In this study, we investigated GLUT expression in a melanoma cell line (B16-F10-Luc2) that was subjected to incremental concentrations of the anthracycline doxorubicin (DOX), ranging from 1 nM to 1 μM. As the cells acquired an MDR phenotype, we observed increased efflux activity and decreased cell proliferation rates. At the proteomic level, our analysis showed that GLUT1 and GLUT3 remain stable over the range of resistance levels, while GLUT2 exhibited minimal expression. Interestingly, GLUT4 was transiently upregulated at the 1 μM resistance level and demonstrated insulin responsiveness. We then evaluated GLUT activity and functionality by comparing glucose uptake under normal and starvation conditions and found that glucose deprivation had a limited impact on uptake in both non-resistant and resistant melanoma. To gain a comprehensive analysis into the genomic regulation of GLUTs and metabolic factors associated with MDR, we performed RNA-seq to reveal differential gene expression across various intermediate levels of DOX resistance. Collectively, our findings provide insights into the modular metabolic adaptations of MDR cancers, which could aid in the development of targeted therapies that address GLUT-related defects with drug resistance. Citation Format: Emily T. Wang, Abbey Michaelson, Amy E. Nielson, Rock J. Mancini. Characterizing glucose transport at incremental stages of chemoresistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6793.