Abstract 5530: Combination of BRAF and ACLY inhibition synergistically reduces melanoma cell viability

Abstract Fifty percent of Melanoma cases harbor the activating BRAF V600E mutation which prompted the development of BRAF inhibitors Vemurafenib, Dabrafenib and Encorafenib, used clinically in combination with MEK inhibitors Trametinib, Cobimetinib and Binimetinib. Together, these agents serve to inhibit the MAPK pathway, but the PI3K/AKT pathway is often upregulated in response to MAPK pathway inhibition which can lead to clinically important treatment resistance. AKT functions in numerous cellular processes including survival, growth, proliferation, invasion and metabolism. With respect to metabolism, AKT activates lipogenesis by direct phosphorylation and activation of the enzyme ATP-Citrate Lyase (ACLY). ACLY expression and activity are elevated in melanoma and are associated with a poor prognosis. A new inhibitor of ACLY, NDI-091143, was recently identified based on the structure of ACLY and was used in this study. A panel of BRAF mutant melanoma cell lines was used to investigate whether combining the ACLY inhibitor NDI-091143 with the BRAF inhibitor Vemurafenib would enhance the latter’s pro-apoptotic effects. Using concentrations of each drug that inhibited cell viability individually by 25%, we found that the combination exhibited synergistic reduction of cell viability in all melanoma lines tested, and similar results were obtained using melanoma cells grown in 3D culture. Normal human keratinocytes treated with the same concentrations of Vemurafenib and NDI-091143 did not exhibit reduced viability. In melanoma cell lines, the combination of BRAF and ACLY inhibition activated the ER stress pathway including phosphorylation of eIF, increased CHOP and ATF4 expression, and induced caspase-mediated apoptosis. In addition, the combination of these agents elicited an increase in reactive oxygen species (ROS) as well as activation of the Jun N-terminal kinase (JNK) pathway, both of which stimulate apoptosis. In vivo assessment of this combination treatment in a zebrafish model of melanoma is underway. Citation Format: Anastasiia Vaska, Michael Ferretti, Daniel A. Ho, Rachel E. Harmon, Robert F. Green, Aaron B. Steiner, Nancy A. Krucher. Combination of BRAF and ACLY inhibition synergistically reduces melanoma cell viability [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 5530.