TY - JOUR T1 - Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress JF - bioRxiv DO - 10.1101/288365 SP - 288365 AU - Peter Tsvetkov AU - Alexandre Detappe AU - Kai Cai AU - Heather R. Keys AU - Zarina Brune AU - Weiwen Ying AU - Prathapan Thiru AU - Mairead Reidy AU - Guillaume Kugener AU - Aviad Tsherniak AU - Sandro Santagata AU - Luke Whitesell AU - John L. Markley AU - Irene M. Ghobrial AU - Susan Lindquist Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/03/24/288365.abstract N2 - The mechanisms used by cancer cells to resist the severe disruption in protein homeostasis caused by proteasome inhibitors remain obscure. Here, we show this resistance correlates with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Employing small molecule screens, we identified a striking overlap between compounds that preferentially impede the growth of proteasome inhibitor-resistant cancer cells and those that block the growth of high OXPHOS cells. Elesclomol potently exhibits both characteristics. Using genome-wide CRISPR/Cas9-based screening, in vitro validation and NMR spectroscopy we identify mitochondrial protein ferredoxin 1 (FDX1), a critical component of mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, as the primary target of elesclomol. In a mouse model of multiple myeloma, inhibition of FDX1 with elesclomol significantly attenuated the emergence of proteasome inhibitor-resistance and markedly prolonged survival. Our work reveals that the mitochondrial Fe-S cluster pathway is a targetable vulnerability in cancers that are resistant to increased proteotoxic burden. ER -