Fatty acid synthase (FASN) is overexpressed in numerous tumor types, including breast carcinomas, and promotes changes in the genetic program controlling lipid biosynthesis. While inhibiting FASN appears to be an attractive therapeutic approach under development, the success of this approach may depend on the identification of tumor subtypes with specific metabolic requirements. Applying a comprehensive profile of circulating tumor cells (CTC) using canonical pathway gene sets, we identified a correlation of metabolic subtypes with breast tumor subtype. A lipogenic subtype is strongly associated with Luminal A subtype, whereas the glycolytic subtype associated with Luminal B tumors. The triple negative subtype was more heterogeneous and had the expression of both sets of gene. Such a difference in the metabolic profile may dictate differential sensitivity to inhibitors targeting de novo lipid synthesis, including FASN. This was supported by in vitro studies using selective FASN inhibitor, TVB-3166. Exposure to TVB-3166 over 14 days incubation in Advanced MEM with 1% charcoal-stripped FBS selectively inhibited growth and viability of Luminal A breast cancer cells, but had no effect on Luminal B subtype. This was further confirmed in short-term patient derived cultures. Mechanistic studies suggest that TVB-3166 quickly disrupts FA synthesis leading to the disruption of the lipid raft architecture and tumor cell death through an apoptotic mechanism. In conclusion, our findings highlight that success of targeting cancer metabolism directly may depend on identification of tumor subtypes with specific metabolic requirements.

Citation Format: Gruslova AB, Chen C-L, Wang C-M, Elledge RM, Kaklamani VG, Lathrop K, Huang TH, Brenner A. FASN inhibition by TVB-3166 associates with breast cancer subtype [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-02.