Abstract B026: Dual inhibition of mitochondrial complex I and GLUT-1 exerts a synergistic effect in advanced prostate cancer models

Abstract Prostate cancer remains a major therapeutic challenge, as resistance to androgen deprivation therapy (ADT) frequently develops and leads to castration-resistant prostate cancer (CRPC). This transition is driven in part by metabolic reprogramming that sustains growth under androgen suppression. While the classical Warburg model emphasizes increased glycolysis and reduced oxidative phosphorylation (OXPHOS), emerging evidence indicates that advanced prostate cancers can exhibit both elevated glycolytic and mitochondrial activity, underscoring metabolic flexibility as a hallmark of resistance. However, the influence of androgen sensitivity on these metabolic pathways remains poorly understood. To address this, we characterized the metabolic features of the paired androgen-sensitive (VCaP) and castration-resistant (VCaP-CR) prostate cancer cell models. Extracellular flux analysis revealed that VCaP cells had higher basal glycolytic and respiratory activity, whereas VCaP-CR cells displayed greater spare respiratory capacity, suggesting enhanced mitochondrial adaptability. These findings highlight that CRPC cells rely more heavily on mitochondrial plasticity to sustain energy production. Utilizing a publicly available transcriptomic dataset, we performed gene set enrichment analysis and found VCaP-CR cells exhibit increased expression of genes involved in glucose uptake and glycolysis. Given these metabolic vulnerabilities, we performed a high-throughput combination screen in two CRPC models to identify agents that synergize with either glucose uptake or mitochondrial complex I inhibition. Using the GLUT1 inhibitor BAY-876 and the complex I inhibitor IACS-010759 as anchor compounds, we combined each inhibitor with a panel of 40 prostate cancer-relevant compounds. Notably, the most striking synergy emerged from the dual combination of BAY-876 and IACS-010759 themselves. Combined treatment rapidly depleted mitochondrial membrane potential and induced apoptosis in both models, revealing co-dependence on glycolytic and oxidative metabolism. To assess nutrient utilization, we quantified glutamine consumption and glutamate secretion under basal and drug-treated conditions. VCaP-CR cells exhibited increased glutamine consumption under dual drug treatment, while VCaP cells secreted more glutamate, suggesting divergent routes of glutamine metabolism. Furthermore, combined inhibition suppressed the lactate accumulation typically observed with complex I inhibitors, indicating that glucose uptake blockade is capable of preventing compensatory glycolysis. These results demonstrate that metabolic adaptation accompanying androgen independence creates a therapeutic vulnerability that can be exploited through dual targeting of glucose and mitochondrial metabolism. Together, these findings provide a mechanistic rationale for combined GLUT1 and complex I inhibition as a strategy to overcome metabolic resilience in CRPC. Citation Format: Spencer S. Gaut, Giulia C. Napoli, Jessica D. Kindrick, Cindy H. Chau, Choh Yeung, Christine M. Heske, Craig J. Thomas, William D. Figg. Dual inhibition of mitochondrial complex I and GLUT-1 exerts a synergistic effect in advanced prostate cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B026.