How EGFR Signalling Drives Cancer

Normal EGFR Signalling: Receptor Activation and Downstream Cascades

EGFR is a transmembrane receptor tyrosine kinase belonging to the ErbB family (EGFR/HER1, HER2/ErbB2, HER3, HER4). When EGF or related ligands bind the extracellular domain, EGFR forms homo- or heterodimers, triggering transphosphorylation of intracellular tyrosine residues. These phosphotyrosines serve as docking sites for adapter proteins — GRB2, SHC, SOS — that activate KRAS by promoting GDP-to-GTP exchange.

Activated KRAS then initiates two major downstream signalling cascades: the BRAF/MEK/ERK (MAPK) pathway, which drives proliferation and differentiation, and the PI3K/AKT/mTOR pathway, which promotes cell survival and protein synthesis. This EGFR→KRAS→BRAF→MEK→ERK signalling progression represents the dominant proliferative cascade activated by receptor tyrosine kinase signalling. Signalling is terminated by EGFR internalisation, dephosphorylation by phosphatases, and GAP-mediated stimulation of KRAS GTPase activity.

Oncogenic EGFR Mutations in Lung Cancer

Activating EGFR mutations occur in the tyrosine kinase domain, predominantly as exon 19 deletions (del19) and the L858R point mutation in exon 21, which together account for ~85% of all EGFR mutations. Both alterations stabilise the active conformation of the kinase, rendering it constitutively active without ligand binding and hypersensitive to EGFR inhibitors.

EGFR mutations occur in approximately 15% of Western and 30–50% of Asian patients with non-small-cell lung adenocarcinoma. They are strongly associated with never-smoker status, female sex, and East Asian ethnicity — an epidemiological pattern that initially prompted their discovery. The clinical significance is profound: EGFR-mutant NSCLC has a fundamentally different biology and treatment trajectory than KRAS-mutant or EGFR-wild-type disease.

Beyond activating mutations, EGFR amplification — increased gene copy number — drives receptor overexpression in glioblastoma and head and neck cancers, with a different mutational spectrum including the EGFRvIII deletion that removes the ligand-binding domain and further promotes constitutive activity.

KRAS: The Most Common Downstream Oncoprotein

KRAS lies immediately downstream of EGFR in the signalling cascade, making KRAS mutations the most clinically consequential determinant of EGFR pathway activation in cancer. Oncogenic KRAS mutations — G12D, G12V, G12C, G13D — impair intrinsic GTPase activity, locking KRAS in the GTP-bound active state and providing constitutive downstream signalling independent of any upstream receptor.

KRAS mutations are found in ~90% of pancreatic cancers, ~40% of colorectal cancers, and ~25% of lung adenocarcinomas. Critically, KRAS mutations render cells completely resistant to anti-EGFR therapies — cetuximab and panitumumab provide no benefit in KRAS-mutant colorectal cancer, mandating RAS testing before prescribing these agents.

The first direct KRAS inhibitors — sotorasib and adagrasib — target the G12C mutation specifically via covalent attachment to the unique cysteine, locking KRAS in the inactive GDP-bound state. Response rates in KRAS G12C NSCLC are ~35–40%, representing a landmark advance in a previously undruggable target.

BRAF and the MEK/ERK Cascade

BRAF is the RAF family kinase most commonly mutated in cancer, with the V600E substitution accounting for ~80% of all BRAF mutations. V600E mimics activation loop phosphorylation, making BRAF constitutively active and capable of signalling as a monomer without requiring dimerisation with CRAF — this mechanistic distinction has important therapeutic implications.

In BRAF V600E tumours, the MEK/ERK cascade runs continuously, driving transcription of cyclin D1 for cell cycle entry, MYC for metabolic reprogramming, and anti-apoptotic BCL2 family members. The therapeutic window for BRAF V600E-selective inhibitors is large in melanoma, with response rates of 60–70% — the highest of any targeted therapy in this disease.

Paradoxical ERK activation — where BRAF inhibitor monotherapy actually activates ERK in RAS-wild-type cells via CRAF dimerisation — was an early mechanistic surprise. This explains why BRAF inhibitors must be combined with MEK inhibitors (trametinib, cobimetinib) to suppress the full pathway and prevent an oncogenic paradox.

PI3K/AKT: A Parallel Survival Pathway

While the RAS/MAPK cascade primarily drives proliferation, EGFR signalling simultaneously activates the PI3K/AKT/mTOR pathway through direct phosphorylation of PIK3CA or indirect activation via RAS. AKT promotes cell survival by phosphorylating and inactivating pro-apoptotic proteins (BAD, FOXO3a), and activates mTORC1 to drive protein synthesis.

PIK3CA hotspot mutations (H1047R, E545K) occur in ~15–20% of NSCLC and are a common co-mutation with EGFR, providing a parallel survival signal that can contribute to EGFR inhibitor resistance. Combined PI3K/EGFR inhibition strategies are under investigation to address this co-activation.

Resistance Mechanisms to EGFR Inhibitors

Acquired resistance to EGFR inhibitors is nearly universal within 12–18 months of treatment. The most common mechanism is the T790M gatekeeper mutation (~60% of cases), which sterically hinders first- and second-generation inhibitor binding. Osimertinib was developed specifically to address T790M and is now used upfront, but C797S and other tertiary EGFR mutations have emerged as osimertinib resistance mechanisms.

Non-EGFR resistance mechanisms include MET amplification (~15%), which activates PI3K/AKT and RAS/MAPK independently of EGFR; KRAS mutations (~3%); BRAF fusion; and histological transformation to small cell lung cancer (~5%) — the latter representing a profound biological reprogramming that fundamentally changes treatment approach.

Serial liquid biopsy to track circulating tumour DNA has transformed resistance monitoring, enabling detection of T790M and other mechanisms months before radiological progression and allowing earlier treatment switches.