Abstract 1520: Obesity delays melanoma resistance to BRAF/MEKi inhibitors and alters melanoma metabolism

Background: Obesity is linked to more aggressive melanoma and impaired anti-tumor immunity. However, obese patients show improved survival on BRAF/MEK inhibitors. Obesity induces endoplasmic reticulum stress (ERS), and BRAF/MEK inhibitors shift metabolism from glucose to fatty acid oxidation (FAO), utilizing CPT1A for cell viability. We hypothesize that obesity-induced metabolic reprogramming causes downregulation of CPT1A, impairing melanoma cell metabolism and potentially contributing to longer tumor progression-free survival (PFS) in obese individuals. Methods: Mice were fed either a standard diet (lean) or a high-fat diet (HFD) to induce obesity. Twelve-week-old mice were subcutaneously injected with 1 × 106 YUMMER 1.7 melanoma cells. Tumors were allowed to grow for 2 weeks, after which the mice were treated with BRAF/MEK inhibitors until tumor resistance was observed. Results: Obese mice treated with BRAF/MEK inhibitors showed delayed tumor recurrence compared to lean mice with a median of 80 days in obese mice versus 28 days in lean mice (log-rank p<0.0001). Tumors from obese mice had elevated DRP1 expression (P<0.05) and increased ER stress markers (XBP1, IRE1A, GRP78, PERK). Metabolic reprogramming, including alterations in melanoma state, fatty acid oxidation (FAO), and glycolysis via the BRAF/MEK pathway, resulted in higher levels of CD36, ACADS, and CPT1 in lean mice compared to obese mice (P<0.05). Conversely, NGFR, MITF, DUSP59, HK2, and GLUT-1 levels were elevated in tumors from obese mice (P<0.05). Conclusions: Our findings suggest that obesity contributes to delayed tumor progression, potentially due to alterations in endoplasmic reticulum and mitochondrial function, which disrupt the expression of key metabolic enzymes. These results underscore the potential of targeting metabolic pathways as a complementary therapeutic approach in melanoma treatment. Citation Format: Mahnoush S. Shafiei, Mackenzie Mayhew, Jacob Sellers, Allan Tsung, Russell Witt. Obesity delays melanoma resistance to BRAF/MEKi inhibitors and alters melanoma metabolism [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 1520.