Sustained activation of EGFR-ERK1/2 signaling limits the therapeutic response to tigecycline-induced inhibition of mitochondrial translation in liver cancer

Abstract Treatment of advanced liver cancer still faces great challenges. Identification of tumor dependencies is important for developing novel therapeutic strategies for liver cancer. Here, we identified mitochondrial translation as a major vulnerability of liver cancer by genome-wide CRISPR screen. Targeting mitochondrial translation by tigecycline showed therapeutic potential in liver cancer. Then, a compounds screen was applied to identify MEK inhibitors as synergistic drugs to tigecycline-insensitive liver cancer cells. Mechanistically, sustained activation of EGFR-ERK1/2-MYC cascade conferred the insensitivity to tigecycline, which was mediated by enhanced secretion of EREG and AREG. Moreover, glycolytic enzymes, such as HK2 and PKM2, and mitochondrial one-carbon enzyme SHMT2 were upregulated to stimulate glycolysis and maintain mitochondrial function, respectively, in a MYC-dependent manner. Tigecycline in combination with MEK inhibitor trametinib or EGFR inhibitor gefitinib showed synergistic antitumor effect in vitro and in vivo. Thus, our study provides a potential therapeutic strategy for liver cancer.