Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Tsvetkov, P.; Detappe, A.; Cai, K.; Keys, H. R.; Brune, Z.; Ying, W.; Thiru, P.; Reidy, M.; Kugener, G.; Tsherniak, A.; Santagata, S.; Whitesell, L.; Markley, J. L.; Ghobrial, I. M.; Lindquist, S.

doi:10.1101/288365

bioRxiv · 10.1101/288365

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Tsvetkov, P.·Detappe, A.·Cai, K.·Keys, H. R.·Brune, Z.·Ying, W.·Thiru, P.·Reidy, M.·Kugener, G.·Tsherniak, A.·Santagata, S.·Whitesell, L.·Markley, J. L.·Ghobrial, I. M.·Lindquist, S.

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Abstract

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.

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Tsvetkov, P., Detappe, A., Cai, K., Keys, H. R., Brune, Z., Ying, W., Thiru, P., Reidy, M., Kugener, G., Tsherniak, A., Santagata, S., Whitesell, L., Markley, J. L., Ghobrial, I. M., Lindquist, S.. 2018-03-24. Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress. https://doi.org/10.1101/288365

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