Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology
First Advisor
Lemmon, Mark
Abstract
The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor, but not in glioblastoma multiform (GBM), where mutations occur exclusively in the extracellular region. In this dissertation, I show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands. Different growth factor ligands stabilize distinct EGFR dimer structures that signal with different kinetics to specify or bias outcome. EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signaling and differentiation. GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, I further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. GBM mutations impair ligand bias by altering the ‘balance of energies’ between dimerization and ligand binding – removing autoinhibitory interactions that normally serve as an energetic barrier to allow distinction between ligand based on the strength of the dimers they induce. This result is generalizable to a subset of EGFR extracellular mutations in other cancers. GBM-equivalent mutations are also found in other EGFR family members, such as ErbB3 and ErbB2, but the mechanism of action in heterodimerization contexts is more complex. My results argue for an important role of altered ligand discrimination by EGFR in cancers, with potential implications for therapeutic targeting.
Recommended Citation
Hu, Chun, "Understanding Distinct Roles of EGFR Family Mutations in Different Cancers" (2022). Yale Graduate School of Arts and Sciences Dissertations. 774.
https://elischolar.library.yale.edu/gsas_dissertations/774
