Loss of MET in the Absence of EGFR Signaling Leads to Hepatic Failure in the Resting Liver

Our recent study (Paranjpe S. et al, Hepatology 2016 Nov;64(5):1711–1724) showed that in mice, combined systemic elimination of EGFR and MET signaling abolishes liver regeneration after partial hepatectomy, leading to liver decompensation and death at 15–18 days post‐surgery. In the current study, we investigated the role of EGFR and MET in resting livers that were not stimulated by hepatectomy. Exon 16 from MET was removed using Tamoxifen IP injections in MET ff/ff :TamCre +/+ mice, preserving the protein but eliminating efficient signaling through the receptor. Canertinib diet (an irreversible pan‐ERB EGFR inhibitor) was used to achieve a complete block in EGFR signaling. Vehicle corn oil injections and normal chow were used for the control animals. Surprisingly, double inhibited mice were sickened by day 10 with most of them dead by day 14. In the double inhibited group, liver to body weight ratios decreased over time in a statistically significant way at every time point tested (days 2, 7 and 10), whereas ratios with individual treatments were not statistically altered. Further, in the combined MET and EGFR elimination group, MET protein was totally absent while EGFR protein was preserved. As Canertinib diet alone did not lead to the complete loss of MET protein, and as Canertinib completely inhibits EGFR signaling, we interpret these results to mean that EGFR signaling normally stabilizes MET protein through a mechanism involving exon 16 and that the complete loss of MET in the double‐inhibited animals is what ultimately leads to liver failure. These results underscore the fundamental contribution of the combined HGF/MET and EGFR signaling pathways to hepatic proliferation, survival and functionality. Support or Funding Information Menten Endowment