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Abstract Introduction: Treating triple-negative breast cancer (TNBC) is challenging due to the lack of clearly defined and targetable biomarkers, and treatment options become increasingly limited with TNBC brain metastases (BM). Since the brain microenvironment has relatively low lipid availability, breast cancer cells that colonize the brain increase their reliance on the endogenous biosynthesis of fatty acids. This reveals a potential metabolic vulnerability that can be targeted, and fatty acid synthase (FASN) inhibition has been shown to decrease breast cancer cell invasion in preclinical models. Methods: In our study, we utilized the TNBC cell line MDA-MB-231-Luc/GFP, its brain-seeking subclone, MDA-MB-231-BR-GFP, and two novel cell lines generated from patient-derived organoids obtained from serial collection of brain-metastatic TNBC resections from the same patient, denoted PDO-BC25 and PDO-BC25-2. Cell lines were screened with FASN inhibitors as single agents vs. combined with SN-38 (topoisomerase I inhibitor) and synergy was assessed by the Chou-Talalay method. To characterize signaling changes with FASN inhibition and identify any off-target signaling, we used a Nanostring metabolic pathways nCounter panel to perform differential expression analysis on cells treated with the FASN inhibitor, TVB-2640, vs. vehicle control across the four cell lines. This panel detects the expression of 768 metabolism-related genes. We used 4 biological replicates per sample and the Benjamini-Hochberg statistical method to control for the false discovery rate after performing a t-test to calculate P-values. In addition, we performed spheroid outgrowth assays to identify any phenotypic impacts of FASN inhibition on spheroid outgrowth. Results: Combinatory drug screening between FASN inhibitors and SN-38 revealed synergy in MDA-MB-231-BR-GFP, PDO-BC25, and PDO-BC25-2, but not in the parental MDA-MB-231-Luc/GFP. The Nanostring nCounter metabolic pathways panel identified direct target engagement where FASN, SCD, and the transcription factor SREBP1 were significantly upregulated in the cells treated with TVB-2640 compared to vehicle control (P-adjusted 0.05). Other upregulated genes were related to the pentose phosphate pathway, nucleotide salvage and synthesis, reactive oxygen species response, amino acid synthesis and transport, and autophagy. Genes that were down-regulated are involved in cell cycle progression, deoxynucleotide synthesis, DNA damage repair, fatty acid oxidation, and cytokine and chemokine signaling. Moreover, despite no decrease in cell viability, TVB-2640 alone was able to slow the outgrowth and invasion of Matrigel-embedded spheroids in a spheroid outgrowth assay. Conclusions: In our study, we have shown that the combination of SN-38 and FASN inhibitors is synergistic in the TNBC brain-seeking cell lines, and that FASN inhibition alone causes on-target transcriptome-level changes and a decrease in spheroid invasion. Next, we plan on testing the brain-metastatic potential of these cell lines in the presence and absence of a FASN inhibitor using an organ-on-chip microfluidic device developed by our lab that mimics the blood-brain barrier, to identify if this strategy has a potential role in prevention of brain metastases. Further studies to refine the molecular basis of the mechanism of action of the combination are underway. Citation Format: Habib Serhan, Liwei Bao, Xu Cheng, Matthew Soellner, Sofia Merajver, Aki Morikawa, Nathan Merrill. Targeting Fatty Acid Synthase in Brain Metastatic Triple-negative Breast Cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-12.
Serhan et al. (Thu,) studied this question.