Abstract 1384: Mitochondrial complex I inhibition enhances chemotherapy efficacy in melanoma

Abstract Background: Melanoma, characterized by the uncontrolled proliferation of melanocytes, is one of the most common types of cancer in the United States. Despite improvement in therapeutics, it remains a formidable adversary in oncology due to its aggressive resistance to treatment and propensity for metastasis. Metabolic reprogramming is a hallmark of cancers implicated in resistance to therapies. Previous efforts have focused on targeting glycolysis, while mitochondrial oxidative phosphorylation (OXPHOS) and TCA metabolism remain underexplored in melanoma research due to limited understanding of contexts in which OXPHOS is required for cancer cell growth and survival. Methods: To determine the impact of chemotherapies (Temozolomide and Cisplatin) on cellular metabolism, metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS) and bioenergetics analyses. Therapeutic responses were studied with chemotherapy in combination with a complex I inhibitor (Phenformin and IACS-010759). In vivo studies investigating the combination of complex I inhibitors and Temozolomide were conducted in immunocompetent C57BL/6J mice. Murine YUMM1.7 melanoma cell allografts were established to evaluate tumor growth and therapeutic efficacy through tumor volume analysis. Results: Our study examined OXPHOS diversity across different melanoma cell lines, identifying those with high and low mitochondrial OXPHOS activity. We found that melanoma cells exhibit significant mitochondrial dependency as evidenced by increased TCA cycle intermediates, ATP production, and oxidative capacity in response to chemotherapy. Additionally, melanoma cells increase mitochondrial electron transport chain (ETC) complex I as an adaptive response to chemotherapy. Pharmacological inhibition of ETC complex I synergizes with conventional anti-melanoma chemotherapy in preclinical models. Furthermore, the combination of complex I inhibitors and Temozolomide proved to be the most effective treatment in vivo, significantly suppressing tumor growth in a murine melanoma model compared to either treatment alone. The combination therapy was well-tolerated, with no observed reduction in body weight, indicating minimal systemic toxicity. Conclusion: These findings underscore the clinical promise of employing mitochondrial complex I inhibition as part of a combined therapeutic approach to enhance chemosensitivity for individuals with advanced and refractory melanoma. Citation Format: Semmer Ali, Mehrdad Zarei, Luke D. Rothermel, Jordan M. Winter. Mitochondrial complex I inhibition enhances chemotherapy efficacy 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 1384.