LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer.
Daniel Dauch (project C02), Lars Zender (project A03) and colleagues identified pharmacologically induced lipotoxicity as a new promising therapeutic strategy for the treatment of liver cancer. The authors found that a combination of Liver X receptor alpha (LXRα)-induced saturated fatty acid synthesis and inhibition of the Raf-1 kinase induced cell death of liver cancer cells owing to a toxic accumulation of saturated fatty acids. Mechanistic studies revealed that Raf-1 binds and activates Stearoyl-CoA desaturase-1 (SCD1), the central enzyme in the conversion of saturated into mono-unsaturated fatty acids. Inhibitors that induce a conformational change of Raf-1 (DFG-out conformation) could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity (oxidative stress, induction of an endoplasmic reticulum stress response and formation of lipid droplets) upon increased fatty acid synthesis in tumors. A combinatorial therapy comprising an LXR Agonist and a DFG-out Raf inhibitor was well tolerated and allowed to overcome therapy resistance in liver cancer.Original article: Rudalska R
, Harbig J, Snaebjornsson MT, Klotz S, Zwirner S, Taranets L, Heinzmann F, Kronenberger T, Forster M, Cui W, d’Artista L, Einig E, Hinterleitner M, Schmitz W, Dylawerska A, Kang T-W, Poso A, T. Rosenfeldt MT, Malek NP
, Bitzer M
, Laufer S, Pichler B, Popov N
, Schulze A, Zender L
*, Dauch D
* (2021) LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat Cancer 2:201-217. *equal contribution and shared last author.