Abstract 6779: The plant derived compound Simalikalactone D is a potent anticancer agent in triple negative breast cancer cells

Abstract Despite recent advances in systemic therapy, Triple Negative Breast Cancer (TNBC)—accounting for 10-20% of breast cancer cases—remains the subtype with the worst prognosis, marked by a high risk of distant recurrence and death; thus, novel treatments are urgently needed for this deadly disease. Simalikalactone D (SKD) is a potential anticancer compound from Simarouba tulae, an endemic plant of Puerto Rico. We observed that the TNBC cells, MDA-MB 231 and MDA-MB 468 respond differently when treated with SKD. Thus, it is critically important to investigate the mechanism of action of SKD in TNBC cells. This study involved a comparative analysis in MDA-MB 231 and MDA-MB 468 cells, and their differential response to treatment with SKD. We performed Tandem Mass Tag (TMT)- based quantitative proteomics, followed by Ingenuity Pathway Analysis (IPA) protein expression analysis to identify distinctly active networks and signaling pathways along with different cellular behaviors between the TNBC cell lines.In the MDA-MB 468 cell line, SKD appeared to play a role in inducing apoptosis through Caspase 3 activation, with apparent PD-1/PD-L1 signaling in Death Receptor pathways. This correlates with reduced cell migration and adhesion in this cell line, which could suggest an apoptotic-mediated loss of integrity. Alternatively, the MDA-MB 231 cells did not show Caspase 3 activation, instead they exhibited an activation of autophagy pathways, including Macroautophagy and Late Endosomal Microautophagy (LEMA). After treatment of cells with SKD, LEMA appeared to act as a compensatory mechanism of survival when Autophagy was impaired. This emphasizes the role of cellular stress responses for maintaining cell viability under SKD treatment.This study highlights the influence of genetic and molecular differences on TNBC cell responses to SKD, reinforcing the clinical importance of personalized medicine. Therapeutic strategies using the genetic and molecular profiles of a patient’s tumor could enhance treatment efficacy and improve outcomes, particularly for aggressive cancers like TNBC. Citation Format: Joshua Nieves, Annelis Sanchez, Claudia Ospina, Pablo Vivas-Mejia. The plant derived compound Simalikalactone D is a potent anticancer agent in triple negative breast cancer cells [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 6779.