Looking back on the history of epidermal growth factor receptor mutations in lung cancer

The discovery of the epidermal growth factor receptor (EGFR) represents a landmark achievement in biomedical science, laying the foundation for one of the most transformative success stories in oncology. From the early isolation of epidermal growth factor (EGF) by Stanley Cohen and colleagues to the cloning of EGFR and its identification as a receptor tyrosine kinase, these pioneering studies revealed its central role in cellular growth and proliferation and ultimately linked EGFR signalling to cancer. Early research demonstrated that aberrant EGFR activity could drive tumourigenesis, prompting the development of monoclonal antibodies and small-molecule inhibitors to block receptor activation. Initial clinical experience with first-generation tyrosine kinase inhibitors, gefitinib and erlotinib, revealed dramatic responses in select patients with non-small cell lung cancer (NSCLC), leading to the discovery of sensitizing EGFR mutations as predictive biomarkers of response. These insights ushered in the era of precision medicine in oncology, with molecular testing and targeted therapies becoming the standard of care in the diagnosis and treatment of lung cancer. Subsequent development of second- and third-generation inhibitors, including osimertinib, has further extended survival for patients with EGFR-mutant NSCLC. Despite ongoing challenges owing to drug resistance, novel therapeutic strategies and rational drug combinations continue to redefine the treatment landscape, such that the treatment of EGFR-driven lung cancer remains a paradigm for the application of precision medicine to cancer. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.