Written by Vered Smith, Freelance Science Writer
Glioblastoma Mutations Impair EGFR Ligand Differentiation
Scientists have discovered that mutations in glioblastoma growth factor receptors impair their ability to discriminate between different ligands.
A paper published in Nature by researchers from Yale University School of Medicine demonstrated that mutations in epidermal growth factor receptors (EGFR) can alter their dimer structure, and impair ligand differentiation. This can cause them to react with an epidermal growth factor (EGF) response to any ligand binding, releasing proliferation promoting signals into the cell. This discovery may have provided a new therapeutic approach for treating glioblastoma multiforme.
Glioblastoma Multiforme
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour in adults. It is also the most aggressive and lethal, with less than 1% of patients living for over 10 years. 24% of GBMs have mutations in the extracellular region of the EGFR protein. However, despite EGFR inhibitors successfully treating lung cancer patients with EGFR mutations, they have not successfully treated GBM. This study resolved the role EGFR mutations play in GBM and discovered their previously unknown method of action.
EGFR Activation
In normal cells, EGFR is activated when a ligand binds and two receptors dimerise. Different ligands induce distinct dimer structure and stability, determining different signalling kinetics, and specifying the cell fate.
High affinity ligands such as EGF (and transforming growth factor-α) bind to EGFR and overcome autoinhibitory domain I–domain II contacts between amino acids R84–A265 and L38–F263 in the receptor. This produces a strong symmetric dimerisation that signals transiently to promote proliferation. Lower-affinity ligands, such as epiregulin (EREG), amphiregulin, and epigen, bind to EGFR but cannot overcome these contacts. They act as partial agonists, inducing a weaker asymmetric dimer structure that leads to sustained signalling and cell differentiation.
GBM Mutations Reduce Ligand Discrimination
The scientists determined that common GBM mutations in EGFR such as R84K, A265V, A265T and L38R disrupt domain I–domain II autoinhibitory interactions. This reduces EGFR’s ability to discriminate between its different ligands. It therefore forms strong dimers even in response to low-affinity ligands.
Using X-ray crystallography, the researchers examined the structure of mutated EGFR. They found that an R84K mutation causes EGFR to form a symmetrical dimer when EREG binds, instead of the normal asymmetric dimer. Furthermore, mutations on A265 (the most commonly mutated residue in GBM), strengthen EREG-induced dimerisation through another mechanism. They reorientate the dimer arm so that it is able to dock, even though the dimer is asymmetric in shape. This remodels the dimerisation contacts, strengthening the asymmetrical association and leading to an EGF-like response.
The researchers proposed that when GBM mutations cause EREG responses to be EGF-like, EREG signalling cannot stimulate cell differentiation of progenitor cells, which may promote glioma formation. This may also explain why EGFR mutations occur early in GBM development, but do not confer a significantly worse prognosis for patients.
This study could lead to the design of a new targeted therapy approach for GBM, as well as other cancers with a similar mechanism.
Image Credit: Canva
