Abstract A008: Pre-diabetic D-glucose exposure promotes EOC progression and cisplatin resistance: Role of BAD associated pathway and potential therapeutic strategy

Abstract

Abstract Prediabetes denotes a condition when blood sugar levels exceed normal thresholds (>7mmol) but have not reached the diagnostic criteria for type 2 diabetes (<11mmol). It positively correlates with diminished progression-free survival and overall survival among women with epithelial ovarian cancer (EOC). This suggests a potential metabolic state associated with prediabetes that may facilitate tumor survival and progression. Moreover, prediabetes is also associated with an increased risk of recurrence and poorer survival outcomes of EOC patients, possibly promoting tumor aggressiveness and resistance to treatment, although the precise mechanisms remain unclear and warrant additional investigation. In this study, we aimed to explore whether prediabetic D-glucose levels accelerate EOC progression and elucidate underlying mechanisms. We also aimed to propose a viable and effective therapy strategy for EOC progression. Various in vitro and ex vivo oncogenic assays were used to assess the effects of prediabetic levels of D-glucose in EOC cells. It was found to stimulate oncogenic phenotypes in EOC cells in a dose-dependent manner. EOC cells exposed to prediabetic levels of D-glucose (8mM) exhibited increased cell survival, enhanced foci formation on monolayer, growth in soft agar, spheroid formation capacity in 3D Matrigel (ex-vivo culture), increased migration and invasion, and resistance to cisplatin compared to those exposed to lower D-glucose doses (4mM). Exposure to 8mM D-glucose led to metabolic alterations associated with cisplatin resistance, including increased D-glucose consumption, elevated ATP production, increased thermogenesis, enhanced glycolytic capacity, and augmented mitochondrial activity. RNA sequencing analysis showed the BCL-2-associated death promoter (BAD) pathway positively correlates with metabolic alterations of EOC cells in 8mM. Prediabetic levels of D-glucose upregulated phosphorylation of BAD at serine (S) 99 residue along with key metabolic enzymes such as ALDH1A1, HK2, PFKP, G6PD, and LDHA. Inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) attenuated 8mM D-glucose effects. Furthermore, forced expression of phosphorylated BADS99 increased oncogenic phenotypes of EOC. The elevated activities of metabolic enzymes associated with BADS99 phosphorylation were observed in EOCs, while this effect was diminished with dephosphorylated BADS99. High-throughput screening identified a combination therapy involving a BADS99 phosphorylation inhibitor and HDAC inhibitors demonstrated higher synergy to stimulate apoptosis in EOC cells. The combined BADS99-HDAC inhibition synergistically enhanced the efficacy of HDAC inhibitors, significantly reducing their IC50 values. It impaired cell survival, viability, anchorage-independent growth, mitochondrial activity, energy production, growth in 3D Matrigel and successfully overcome cisplatin resistance of EOC cell lines and a patient-derived cell line (AFC). This synergistic therapeutic approach offers a promising strategy for exploiting synthetic lethality in treating EOC patients. Citation Format: Jing Huang, Xi Zhang, Peng Huang, Basappa Basappa, Tao Zhu, Peter E. Lobie, Vijay Pandey. Pre-diabetic D-glucose exposure promotes EOC progression and cisplatin resistance: Role of BAD associated pathway and potential therapeutic strategy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A008.