Diverging roles of EGFR and MET in acetaminophen-induced acute liver injury

Acetaminophen (APAP) overdose is the topmost cause of acute liver failure (ALF) in the United States, with N-
acetylcysteine (NAC) as the only available pharmacological treatment. NAC is effective only in early presenting
patients, but majority of these patients seek medical attention late. Thus, there is an unmet clinical need to
explore alternative pharmacological approaches targeting later stages of ALF, such as by inhibiting progression
of injury or by boosting the compensatory liver regeneration. Growth factor receptors, MET and EGFR, are
considered essential for liver regeneration after partial hepatectomy (PH), but their roles in the clinically
relevant model of APAP-induced liver injury (AILI) remain underexplored. Unlike PH, massive liver injury and
inflammation during AILI greatly govern its pathophysiology and our previous studies have shown that roles of
these growth factor receptors in AILI model cannot be presumed identical to that known in regeneration of a
healthy liver after PH. In fact, our previously published study indicated an unexpected role of early EGFR
activation in aggravating AILI, in contrast to its conventional role in hepatocyte proliferation during
regeneration. We found that EGFR activation correlated with the severity of injury and treatment with EGFR
inhibitor (canertinib) almost completely abolished AILI in mice. Contrary to EGFR, our preliminary studies
indicate that MET is involved in actively suppressing progression of liver injury during AILI, apart from its role
in promoting liver regeneration. Thus, our overarching hypothesis is that EGFR and MET play diametrically
opposite roles in acute liver injury after APAP overdose, as opposed to their conventionally known and
functionally similar roles in hepatocyte proliferation. In contrast to their similar roles in liver regeneration,
MET directly suppresses and, paradoxically, EGFR aggravates acute liver injury in the AILI model. To establish
the paradigm-shift proposed by our initial findings, our specific aims 1 and 2 will comprehensively investigate
the roles of EGFR and MET, respectively, in liver injury and compensatory regeneration after APAP overdose,
utilizing hepatocyte-specific knock out and receptor-activation strategies. Further, we will investigate the
mechanisms underlying these novel roles of growth factor receptors in AILI. For therapeutic relevance, the
effects of clinically-approved EGFR inhibitor (afatinib) and interventions targeting MET will be investigated on
AILI, especially focusing on clinically relevant late intervention, when NAC is ineffective. Lastly, for human
relevance, we will also investigate the effects of our interventions and validate mechanisms in well-
characterized primary human hepatocyte model of AILI. These studies will not only elucidate regenerative role
of MET and EGFR, for the first time in a clinically significant ALF model but will also reveal insights into the
novel aspect of growth factor receptor biology related to acute liver injury. Moreover, successful completion of
these studies will be useful to determine the potential of repurposing a clinically available EGFR inhibitor
and/or interventions targeting MET to treat APAP-induced ALF.

Grant Number: 5R01DK135566-03
NIH Institute/Center: NIH
Principal Investigator: Bharat Bhushan