%0 Journal Article %A Peter Tsvetkov %A Alexandre Detappe %A Kai Cai %A Heather R. Keys %A Zarina Brune %A Weiwen Ying %A Prathapan Thiru %A Mairead Reidy %A Guillaume Kugener %A Aviad Tsherniak %A Sandro Santagata %A Luke Whitesell %A John L. Markley %A Irene M. Ghobrial %A Susan Lindquist %T Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress %D 2018 %R 10.1101/288365 %J bioRxiv %P 288365 %X 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. %U https://www.biorxiv.org/content/biorxiv/early/2018/03/24/288365.full.pdf