Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

• DOI: 10.1038/s41419-021-04262-x
• Publication Date: 2021-10-21T08:03:23Z
• Authors: Barbara Schroeder; Travis Vander Steen; Ingrid Espinoza; Chandra M. Kurapa...; Zeng Hu; Fernando Martín S...; Kevin Regan; Elisabet Cuyàs; X. Wei Meng; Sara Verdura; Aina Arbusà; Paula A. Schneider; Karen S. Flatten; George Kemble; Joan Montero; Scott H. Kaufmann; Javier A. Menendez; Ruth Lupu
• Keywords: Puma; Priming (agriculture)

Abstract Inhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in last decade as potential targeted cancer therapies. However, little is known about molecular determinants cell sensitivity to FASN inhibitors (FASNis), which a major roadblock their therapeutic application. Here, we find that pharmacological starvation endogenously produced FAs previously unrecognized metabolic stress heightens mitochondrial apoptotic priming and favors death induction by BH3 mimetic inhibitors. Evaluation decision circuits controlled BCL-2 family proteins revealed inhibition accompanied upregulation pro-death BH3-only BIM, PUMA, NOXA. Cell triggered inhibition, causally involves palmitate/NADPH-related redox imbalance, markedly diminished concurrent loss BIM or suggesting activity controls survival fine-tuning only proteins-dependent threshold for apoptosis. results heightened apoptosis priming, shifting cells toward primed-for-death state “addicted” anti-apoptotic protein BCL-2. Accordingly, co-administration FASNi synergistically augments apoptosis-inducing dual BCL-X L /BCL-2 inhibitor ABT-263 (navitoclax) specific BH3-mimetic ABT-199 (venetoclax). however, fails sensitize breast MCL-1- -selective such S63845 A1331852. A human xenograft model evidenced oral administration clinically available drastically sensitizes FASN-addicted tumors ineffective single-agents navitoclax venetoclax vivo. In summary, novel FASN-driven facet mechanistically links redox-buffering mechanism intrinsic cells. Combining next-generation FASNis with BCL-2-specific mimetics directly activate machinery might generate more potent longer-lasting antitumor responses clinical setting.