EGFR Pathway

The epidermal growth factor receptor (EGFR/ErbB1/HER1) is a transmembrane receptor tyrosine kinase activated by ligands including EGF, TGF-alpha, and amphiregulin. Ligand binding induces receptor homo- or heterodimerisation with other ErbB family members, kinase domain activation, and downstream signalling through RAS/MAPK (driving proliferation) and PI3K/AKT/mTOR (promoting survival and drug resistance). In NSCLC, activating mutations in the EGFR kinase domain — predominantly exon 19 deletions and the L858R point mutation in exon 21 — create a constitutively active receptor that drives oncogenic signalling independently of ligand, rendering tumours highly sensitive to EGFR TKI therapy.

Three generations of EGFR TKIs have been developed sequentially in response to acquired resistance mechanisms. First-generation reversible inhibitors (erlotinib, gefitinib) established proof of concept but were universally superseded by the T790M gatekeeper mutation in approximately 50-60% of patients after 9-12 months. Second-generation irreversible inhibitors (afatinib, dacomitinib), which covalently bind EGFR and also inhibit HER2 and HER4, show modest T790M activity but are limited by toxicity from pan-ErbB inhibition. Osimertinib, a third-generation irreversible inhibitor designed to spare wild-type EGFR, is now the standard first-line treatment for EGFR-mutant NSCLC following the FLAURA trial, with superior PFS and CNS penetration.

In colorectal cancer and head and neck squamous cell carcinoma, EGFR is a target for anti-EGFR monoclonal antibodies (cetuximab — chimeric IgG1, panitumumab — fully human IgG2). In metastatic colorectal cancer, anti-EGFR efficacy is restricted to tumours with wild-type RAS and BRAF (left-sided primary tumours show greater benefit), as downstream RAS mutations render EGFR blockade ineffective. Exon 20 insertion mutations in NSCLC confer primary resistance to first- and second-generation TKIs and represent an emerging therapeutic target for dedicated exon 20 inhibitors.