# Functional loss of ERBB receptor feedback inhibitor 1 (MIG6) promotes glioblastoma tumorigenesis by aberrant activation of epidermal growth factor receptor (EGFR)

## TL;DR

This study shows that loss of MIG6 function leads to abnormal activation of EGFR, contributing to glioblastoma growth and suggesting MIG6-related biomarkers for targeted therapies.

## Contribution

The study reveals how MIG6 loss or mutation disrupts EGFR inhibition, offering new biomarkers for glioblastoma treatment.

## Key findings

- Reduced MIG6 activity leads to aberrant EGFR activation in glioblastoma.
- ERRFI1 mutations impair MIG6's ability to suppress EGFR at multiple levels.
- ERRFI1 mutation status and MIG6 expression may serve as biomarkers for EGFR-targeted therapies.

## Abstract

Dysregulation of epidermal growth factor receptor (EGFR) is one of the most common mechanisms associated with the pathogenesis of various cancers. Mitogen‐inducible gene 6 [MIG6; also known as ERBB receptor feedback inhibitor 1 (ERRFI1)], identified as a feedback inhibitor of EGFR, negatively regulates EGFR by directly inhibiting its kinase activity and facilitating its internalization, subsequently leading to degradation. Despite its proposed role as an EGFR‐dependent tumor suppressor, the functional consequences and clinical relevance in cancer etiology remain incompletely understood. Here, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR‐dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. We propose that the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR‐targeted cancer therapies, including glioblastoma.

EGFR dysregulation is one of the most common mechanisms in glioblastoma pathogenesis. Here, we identified that reduced MIG6 activity, stemming from lower protein expression or specific ERRFI1 loss‐of‐function mutations, causes aberrant EGFR activation by impairing multiple negative‐feedback‐inhibition mechanisms. This finding suggests that ERRFI1 mutation status and MIG6 expression levels could potentially serve as biomarkers for guiding EGFR‐targeted glioblastoma therapies.