The EGFR signalling pathway converts extracellular EGF binding into intracellular proliferative and survival signals via the KRAS–RAF–MEK–ERK cascade. In cancer, activating mutations in EGFR (exon 19 deletions, L858R) or constitutively activating KRAS mutations (G12C, G12D, G12V) decouple this cascade from upstream regulation, driving uncontrolled tumour cell proliferation. Understanding the EGFR–KRAS pathway mechanism is essential for interpreting why EGFR inhibitors fail in KRAS-mutant cancers, how resistance emerges, and how targeted therapies are selected across NSCLC, colorectal, and pancreatic cancers.
The EGFR signalling pathway begins when EGF or related ligands (TGF-α, amphiregulin, epiregulin) bind the extracellular domain of EGFR (ErbB1/HER1), inducing receptor dimerisation and trans-autophosphorylation of intracellular tyrosine residues. Phospho-Tyr1068 recruits the GRB2–SOS1 adaptor complex to the membrane, where SOS1 catalyses GDP→GTP exchange on membrane-anchored KRAS (and HRAS, NRAS). GTP-bound KRAS adopts an active conformation that recruits BRAF and CRAF kinases, initiating the RAF→MEK→ERK phosphorylation cascade. Nuclear ERK activates transcription factors ELK1, MYC, and c-FOS, which drive CCND1 (cyclin D1) expression and G1/S cell cycle entry. PI3K/AKT/mTOR survival signalling is simultaneously activated through p85 SH2 recruitment to phospho-Tyr992 and via direct GTP-KRAS binding to the p110α catalytic subunit of PI3K, reinforcing tumour cell survival independent of the MAPK cascade.
The EGFR signalling pathway begins when EGF or related ligands (TGF-α, amphiregulin, epiregulin) bind the extracellular domain of EGFR (ErbB1/HER1), inducing receptor dimerisation and trans-autophosphorylation of intracellular tyrosine residues. Phospho-Tyr1068 recruits the GRB2–SOS1 adaptor complex to the membrane, where SOS1 catalyses GDP→GTP exchange on membrane-anchored KRAS (and HRAS, NRAS). GTP-bound KRAS adopts an active conformation that recruits BRAF and CRAF kinases, initiating the RAF→MEK→ERK phosphorylation cascade. Nuclear ERK activates transcription factors ELK1, MYC, and c-FOS, which drive CCND1 (cyclin D1) expression and G1/S cell cycle entry. PI3K/AKT/mTOR survival signalling is simultaneously activated through p85 SH2 recruitment to phospho-Tyr992 and via direct GTP-KRAS binding to the p110α catalytic subunit of PI3K, reinforcing tumour cell survival independent of the MAPK cascade.
EGFR–KRAS–BRAF Signalling — Driver Mutations and Therapeutic Targets
EGFR, KRAS and BRAF alterations can converge on MEK/ERK while creating different testing and treatment questions.
| Signalling state | Altered node | Pathway effect | Interpretive boundary |
|---|---|---|---|
| Normal ligand-driven signalling | No oncogenic driver required | EGF binding transiently activates EGFR, RAS–RAF–MEK–ERK and parallel PI3K/AKT and PLCγ/PKC branches. | Signal strength and duration remain controlled by ligand availability, phosphatases, receptor internalisation and RAS GTP hydrolysis. |
| EGFR-driven signalling | EGFR exon 19 deletion or L858R | The receptor kinase signals with reduced dependence on ligand and continues to feed RAS/MAPK and survival pathways. | In NSCLC, the exact EGFR variant, specimen, stage and current regulatory context determine how the result is interpreted. |
| KRAS-driven signalling | KRAS G12, G13 or Q61 variants | Reduced GTP hydrolysis sustains RAF–MEK–ERK output downstream of receptor input. | Upstream EGFR blockade may not suppress the downstream signal; the predictive meaning depends on tumour type and treatment setting. |
| BRAF-driven signalling | BRAF V600E or another BRAF class | RAF–MEK–ERK signalling is activated at the RAF node; non-V600 alterations can behave differently from V600E. | BRAF class and tumour lineage matter. Evidence from melanoma, colorectal cancer and NSCLC should not be treated as interchangeable. |
EGF binds bivalently across domains I and III of the EGFR extracellular region, stabilising a transition from the autoinhibited 'tethered' conformation (in which domains II and IV form an intramolecular tether) to the 'extended' conformation that exposes the domain II dimerisation arm. This structural shift increases EGFR's affinity for homo- and heterodimerisation with ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) by ~100-fold. In EGFR-overexpressing cancers, elevated receptor density increases the probability of spontaneous ligand-independent dimerisation, bypassing the requirement for EGF.
EGFR dimerisation positions the intracellular kinase domains in an asymmetric head-to-tail configuration. The C-lobe of one kinase (the 'activator') contacts the N-lobe of the partner kinase (the 'receiver'), allosterically repositioning the activation loop of the receiver into the active DFG-in conformation without direct phosphoryl transfer between activation loops. The T790M gatekeeper substitution can reduce sensitivity to earlier EGFR inhibitors, but biochemical work indicates that increased ATP affinity is a major mechanism rather than a simple steric blockade. The natural asymmetric activation mechanism remains intact.
The activated receiver kinase trans-phosphorylates the C-terminal tail of the activator kinase on six key tyrosines: Tyr992, Tyr1045, Tyr1068, Tyr1086, Tyr1148, and Tyr1173. Each phosphotyrosine recruits distinct SH2-domain effectors: Tyr1068 recruits GRB2 (→RAS/MAPK activation), Tyr992 and Tyr1173 recruit PLCγ1 (→PKC/calcium signalling), Tyr1045 recruits c-CBL (→receptor ubiquitination and lysosomal degradation), and Tyr1068/1086 recruit SHC adaptors (→amplified GRB2–SOS recruitment). EGFR exon 19 deletions and L858R mutations increase autophosphorylation kinetics ~10-fold by destabilising the inactive kinase conformation, explaining their ligand-independence.
GRB2 constitutively binds SOS1 via its two flanking SH3 domains binding proline-rich regions of SOS1; this GRB2–SOS1 complex is pre-assembled in the cytoplasm. Phospho-Tyr1068-EGFR recruits the complex en bloc via GRB2's SH2 domain, concentrating SOS1 at the inner leaflet of the plasma membrane where prenylated KRAS resides. Membrane localisation is essential: KRAS is constitutively membrane-anchored via C-terminal farnesylation and polybasic region electrostatics, so SOS1's GDP-exchange activity on KRAS requires co-localisation at the same membrane compartment. The SHC→GRB2→SOS1 route provides a parallel, amplified input at lower EGFR activation thresholds.
Membrane-localised SOS1 inserts its CDC25 catalytic domain into the nucleotide-binding cleft of KRAS, displacing the switch I loop and opening the nucleotide pocket to solvent. GDP dissociates rapidly (intrinsic rate ≪1 min⁻¹; SOS1-catalysed rate ~100-fold faster), and GTP — present at ~10-fold higher cytoplasmic concentration than GDP — rebinds and resets switch I and II loops into the active closed conformation. GTP-KRAS presents a dramatically remodelled effector-binding surface with high affinity for BRAF and CRAF RBDs (Kd ~20 nM), the p110α RBD of PI3K, and RALGDS. Oncogenic KRAS mutations (G12C, G12D, G12V, G13D) impair GTP hydrolysis by sterically obstructing the arginine finger of GAP proteins, locking KRAS in this active state permanently.
GTP-KRAS recruits BRAF and CRAF (RAF1) to the plasma membrane via their RAS-binding domains (RBDs) and cysteine-rich domains (CRDs). Membrane localisation relieves autoinhibitory 14-3-3 contacts at BRAF Ser365/Ser729, enabling BRAF–BRAF homodimerisation or the more potent BRAF–CRAF heterodimerisation. Dimerisation releases N-terminal regulatory inhibition and positions the DFG motif into the active 'DFG-in' kinase conformation. BRAF V600E bypasses this mechanism entirely: the V600E substitution disrupts an intramolecular hydrophobic interaction that stabilises the inactive monomer, enabling constitutive kinase activity independent of RAS-mediated dimerisation — explaining why BRAF V600E tumours retain RAF/MEK/ERK signalling even when upstream RAS is wild-type.
Active RAF phosphorylates MEK1 (MAP2K1) at Ser218 and Ser222, and MEK2 (MAP2K2) at Ser222 and Ser226, within their activation segment. MEK is a structurally constrained dual-specificity kinase with exceptionally narrow substrate specificity — its only known physiological substrates are ERK1 and ERK2. MEK achieves dual phosphorylation of ERK in a single processive event, phosphorylating first Tyr and then Thr without releasing the substrate. This narrow specificity is the mechanistic basis for the high selectivity of allosteric MEK inhibitors (trametinib, cobimetinib, binimetinib), which stabilise an inactive MEK conformation adjacent to the ATP-binding site without competing with ATP.
Doubly-phosphorylated ERK1 (pThr202/pTyr204) and ERK2 (pThr185/pTyr187) undergo a conformational change that enables homodimerisation and nuclear import via importin-independent mechanisms involving nuclear pore components. Nuclear ERK phosphorylates ELK1 (Ser383/Ser389) to drive c-FOS transcription, phosphorylates and stabilises MYC (Ser62), and activates RSK2 (which phosphorylates CREB at Ser133). The resulting transcriptional programme upregulates CCND1 (cyclin D1), CDK4, anti-apoptotic BCL-XL, and ribosome biogenesis genes — directly coupling EGFR→KRAS→ERK signal amplitude to G1/S cell cycle commitment. Cytoplasmic ERK simultaneously phosphorylates RSK1/2, MNK1/2 (→eIF4E-mediated cap-dependent translation), and cytoskeletal proteins, integrating proliferative, translational, and migratory outputs of the EGFR–KRAS signal.
EGFR and KRAS alterations activate overlapping signalling networks at different nodes. EGFR activating mutations — most commonly exon 19 deletions and L858R — produce ligand-independent receptor signalling and occur in roughly 10–15% of NSCLC in Western populations, with higher prevalence in East Asian populations and enrichment in adenocarcinoma and never-smokers. KRAS oncogenic mutations impair intrinsic and GAP-stimulated GTP hydrolysis, sustaining RAS–MAPK signalling independently of receptor input. This downstream activation explains why RAS mutation status predicts lack of benefit from cetuximab or panitumumab in metastatic colorectal cancer. EGFR and KRAS driver mutations are often mutually exclusive in treatment-naive lung adenocarcinoma, but rare co-occurrence and acquired subclonal KRAS alterations are documented; the tumour type, treatment, allele, and clonal context therefore matter.
EGFR-targeted therapies exploit specific receptor dependencies. Reversible TKIs such as erlotinib and gefitinib compete with ATP; afatinib and dacomitinib irreversibly modify Cys797; and osimertinib covalently targets Cys797 while retaining activity against sensitising EGFR mutations and T790M. Treatment results depend on line of therapy and regimen, so progression-free-survival figures should be read in the context of the cited trial rather than as a property of the drug alone. For cetuximab and panitumumab in metastatic colorectal cancer, RAS testing is required for treatment selection under drug labels and professional guidelines because activating KRAS or NRAS mutations predict lack of benefit. In NSCLC, broad molecular testing distinguishes EGFR-, KRAS-, ALK-, ROS1-, MET-, and other driver-defined disease. Acquired osimertinib resistance is heterogeneous and can include MET amplification, EGFR C797S, histologic transformation, and less common downstream alterations. KRAS G12C inhibitors exploit a switch-II pocket in GDP-bound KRAS; anti-EGFR combinations are clinically validated in previously treated KRAS G12C-mutant metastatic colorectal cancer, not as a universal strategy across KRAS-mutant tumours.
What does EGFR do in cancer?
EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase that, when activated by EGF ligand, dimerises and autophosphorylates intracellular tyrosine residues to initiate the RAS/MAPK and PI3K/AKT proliferative and survival cascades. In cancer, EGFR is dysregulated through activating kinase domain mutations (exon 19 deletions, L858R), gene amplification (up to 40-fold in glioblastoma), or autocrine ligand loops — causing ligand-independent, constitutive pathway activation that drives uncontrolled proliferation. EGFR mutations are the primary oncogenic driver in 10–15% of NSCLC cases and define a patient population with high sensitivity to EGFR TKIs.
How does KRAS affect EGFR signalling?
KRAS is a major downstream effector of EGFR. Normally, EGFR recruits GRB2–SOS1 to promote GDP-to-GTP exchange on KRAS. Activating KRAS mutations reduce GTP hydrolysis and sustain downstream signalling. In metastatic colorectal cancer, activating RAS mutations predict lack of benefit from cetuximab or panitumumab. That relationship should not be generalised to every EGFR-directed drug or tumour type, because receptor dependence, mutation allele, combination therapy, and tissue context differ.
What is the EGFR–KRAS signalling pathway step-by-step?
The EGFR–KRAS signalling pathway: (1) EGF binds EGFR extracellular domain → (2) receptor dimerisation and asymmetric kinase activation → (3) tyrosine autophosphorylation (Tyr1068, Tyr992, etc.) → (4) GRB2–SOS1 recruited to phospho-Tyr1068 → (5) SOS1 catalyses GDP→GTP exchange on membrane-anchored KRAS → (6) GTP-KRAS recruits and activates BRAF/CRAF via RBD → (7) RAF phosphorylates MEK1/2 (Ser218/Ser222) → (8) MEK dually phosphorylates ERK1/2 (Thr202/Tyr204 on ERK1; Thr185/Tyr187 on ERK2) → (9) Nuclear ERK activates ELK1, MYC, and c-FOS, driving cyclin D1 expression and G1/S entry. Simultaneously, GTP-KRAS and phospho-Tyr992-EGFR activate PI3K→AKT→mTOR survival signalling in parallel.
Why are EGFR inhibitors ineffective in some cancers?
EGFR inhibitors fail primarily in tumours with downstream activating mutations that bypass EGFR. KRAS mutations (G12C/D/V/R) are the most common mechanism — constitutively GTP-bound KRAS activates RAF→MEK→ERK independently of EGFR status. Secondary resistance to EGFR TKIs involves EGFR T790M (addressed by osimertinib), C797S (prevents covalent osimertinib binding), MET amplification, HER2 amplification, BRAF V600E, and PIK3CA/PTEN alterations that sustain survival through AKT/mTOR even when MAPK is suppressed. These co-occurring alterations mean single-agent EGFR blockade is insufficient in molecularly heterogeneous tumours.
What is the difference between EGFR and KRAS mutations in lung cancer?
EGFR and KRAS alterations activate the same network at different levels: EGFR is the receptor input, whereas KRAS is a downstream molecular switch. Activating EGFR and KRAS drivers are negatively associated in treatment-naive lung adenocarcinoma cohorts, but rare co-occurrence is documented, so 'mutually exclusive' is a useful pattern rather than an absolute rule. The exact allele, tumour lineage, clonality and treatment history determine the clinical meaning.
What role does the EGFR–KRAS pathway play in pancreatic cancer?
In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations — predominantly G12D (~35%), G12V (~18%), G12R (~16%) — are the initiating oncogenic event present in >90% of cases. EGFR is overexpressed in ~30–40% of PDAC and contributes upstream activation, but the dominant signal runs through constitutively active mutant KRAS, rendering cetuximab-based anti-EGFR strategies ineffective. Sotorasib and adagrasib cover only KRAS G12C (rare in PDAC: <2%), while non-covalent G12D inhibitors (MRTX1133) and pan-KRAS inhibitors (RMC-6236) targeting multiple KRAS mutations simultaneously are in clinical trials for PDAC.
Move from the complete pathway to a gene, variant or tumour-specific interpretation.
Gene function, aliases and cancer relevance.
Testing, sensitising mutations and resistance.
Variant meaning and testing boundaries.
Exon 21 biology and evidence context.
Gatekeeper biology and resistance testing.
Alleles, tumour context and direct inhibition.
RAF activation across tumour types.
The wider RAS–RAF–MEK–ERK network.
Understand sensitising EGFR mutations in NSCLC, how molecular testing is interpreted, and how T790M, C797S, MET amplification and other resistance mechanisms differ.
A clear, evidence-linked guide to EGFR exon 19 deletions in non-small-cell lung cancer: what the alteration is, how it is tested, and what the FDA label does and does not establish.
Understand EGFR L858R in exon 21, how laboratories detect it, why it is grouped with sensitising EGFR alterations, and where treatment claims must stay label-specific.
Learn how EGFR T790M can alter drug binding after an earlier EGFR therapy, why resistance testing is contextual, and how to read the FDA label without overgeneralising.
How KRAS mutations lock the EGFR→KRAS→BRAF→MEK→ERK cascade in constitutive activation, why KRAS was undruggable for 40 years, how G12C covalent inhibitors work, and combination strategies overcoming EGFR-mediated resistance.
How BRAF V600E activates MEK–ERK signalling, why treatment evidence differs by tumour lineage, and how feedback and resistance shape interpretation.
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