Journal Club

YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis

EMBO Mol Med. 2021 Oct 19;e14351.

Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.

• The transcription factors YAP and TAZ stabilize ATF4 by promoting its nuclear import to cooperatively induce expression of SLC7A11, a cystine importer critical for glutathione synthesis.

• Glutathione synthesis and homeostasis are required to repress ferroptosis and to maintain Sorafenib resistance in liver cancer cells.

• Inhibition of Glutathione synthesis re-sensitizes Sorafenib-resistant cancer cells to Sorafenib therapy, which then induces ferroptosis and represses tumor growth in murine liver cancer models.

• Pharmacological repression of the anti-oxidant pathways regulated by YAP/TAZ and ATF4 could re-sensitize therapy-resistant liver cancers to Sorafenib treatment.