The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Glioblastoma , Lung Neoplasms , Humans , Glioblastoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation
Takayasu arteritis (TA) is a large vessel arteritis that predominantly affects the aorta and its major branches. Its association with tuberculosis (TB) has been described in the literature. This association poses a diagnostic and therapeutic challenge, especially in TB-endemic areas. We report a case of a young Ethiopian female patient who was diagnosed with TA associated with TB. We discuss the diagnostic and therapeutic challenges of this association.
