Targeting EGFR in lung cancer: lessons in signal transduction and treatment-induced mutagenesis

The epidermal growth factor receptor (EGFR) plays pivotal role in cancer promotion and progression, particularly in non-small cell lung cancer (NSCLC), where activating EGFR mutations drive tumour growth. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have improved patient survival rates, but resistance inevitably develops through mechanisms ranging from secondary mutations to bypass signalling pathways and histological transformation. A key factor in resistance development is the emergence of drug-tolerant persister cells, a rare population with epigenetic alterations that precede permanent, mutation-driven resistance. These cells evade apoptosis by triggering an evolutionarily conserved survival mechanism known as SOS. The SOS process is accompanied by increased reactive oxygen species, DNA breaks, defective DNA repair and activation of mutation-inducing factors like error-prone DNA polymerases and imbalanced dNTP pools. In patients receiving TKIs, this adaptive response probably drives the formation of extrachromosomal circular DNA and various genomic aberrations, collectively resembling chromothripsis. The aberrations include not only point mutations and gene amplifications but also indels and gene fusions. To overcome resistance, new therapeutic strategies are being explored, such as fourth-generation TKIs, allosteric inhibitors, degraders and bispecific antibodies. Ongoing research into EGFR biology offers the potential to transform EGFR-positive NSCLC from a lethal disease into a chronic, manageable condition. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.