A powerful drug combination strategy targeting BRAF-mutant melanoma.

Abstract

3152 Background: BRAF inhibitors, such as vemurafenib and dabrafenib, are effective in treating patients with melanoma harboring (V600E) BRAF mutations. These drugs block the activity of the mutated BRAF protein, which impacts the development and progression of melanoma. Despite initial efficacy, drug resistance reliably occurs leading to disease relapse. Here we show how BRAF inhibitors cause metabolic reprogramming in melanoma cells to achieve drug resistance and promote cell survival. Previously we demonstrated that wild-type isocitrate dehydrogenase 1 (wtIDH1) supports mitochondrial function and maintains redox homeostasis in melanoma, and that an FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtIDH1 inhibitor. Thus, we hypothesized that wtIDH1 inhibition would synergize with BRAF inhibition. Methods: Metabolomic profiling using LC-MS determined the impact of BRAF inhibition on cellular metabolism. Cell viability was assessed by PicoGreen in drug combination assays. Synergism was calculated using the Bliss-Independence dose-response model for drug interaction. In vivo modeling of AG-120 in combination with BRAF inhibition used melanoma cell xenografts in athymic nude mice for tumor volume analyses, and survival studies were performed in both immunocompetent C57BL/6J mice (murine YUMM1.7 cells) and immunocompromised athymic nude mice (human A375 cells). Results: Metabolomics data suggest that BRAF-mutated melanoma cells treated with BRAF inhibitors increased oxidative metabolism and mitochondrial dependence (i.e., survival adaptations). These alterations suggest an opportunity for mitochondrial inhibitors to improve drug efficacy. Targeting wtIDH1 with AG-120 in combination with dabrafenib significantly reduced melanoma cell viability. A positive synergy score and Bliss score greater than 1 indicate that the combined treatment was more effective in reducing cell viability than either treatment alone. Further, the combination of AG-120 and dabrafenib was the most effective in vivo, reducing tumor growth in the BRAF-mutated melanoma xenograft model, and improving mouse survival compared to monotherapy controls. Mice tolerated combination therapy with no reduction in body weight observed. Conclusions: Our findings indicate that dual inhibition of mutated BRAF and wild-type IDH1 represents a novel treatment strategy for BRAF-mutated melanomas, with potential for application to other BRAF-mutated cancers (e.g., colon, hepatobiliary, thyroid, etc.).