Structure of EGFR
EGFR (HER1/ErbB1) is a transmembrane glycoprotein receptor in the ErbB family of receptor tyrosine kinases (RTKs).
- Extracellular domain (ECD): Binds epidermal growth factor (EGF) and related ligands.
- Transmembrane domain (TMD): Anchors EGFR in the cell membrane.
- Intracellular tyrosine kinase domain (TKD): Responsible for autophosphorylation and downstream signaling.
- C-terminal tail: Contains phosphorylation sites for interaction with intracellular signaling molecules.
Function of EGFR
EGFR plays a crucial role in cell proliferation, differentiation, survival, and migration.
- Normal function: Tissue repair, embryonic development, and immune response.
- Dysregulation: Overexpression or mutation leads to cancer progression, especially in non-small cell lung cancer (NSCLC), colorectal cancer, and glioblastoma.
EGFR Signaling Pathway
- Ligand Binding: EGF, TGF-α, or other ligands bind EGFR, inducing dimerization.
- Autophosphorylation: Activation of intracellular kinase domain.
Downstream Signaling Activation:
- PI3K-AKT Pathway: Promotes cell survival and anti-apoptosis.
- Ras-Raf-MEK-ERK Pathway: Enhances proliferation.
- JAK-STAT Pathway: Regulates inflammation and immune response.
- PLCγ-PKC Pathway: Increases cell motility and invasion.
- Oncogenic Role: Mutations (e.g., L858R, exon 19 deletions) lead to constitutive activation, driving uncontrolled cancer growth.
Market Prospects of EGFR Inhibitors
- Global market value: Estimated at $10.3 billion in 2023, projected to reach $15 billion by 2030.
- Growth drivers: Rising incidence of NSCLC and colorectal cancer, increasing adoption of targeted therapy, and advancements in resistance-overcoming drugs.
- Key companies: AstraZeneca, Roche, Merck, Amgen, Takeda, Eli Lilly.
- Future trends: Development of 3rd and 4th generation EGFR inhibitors, combination therapies, and novel bispecific antibodies.
FDA-Approved EGFR-Targeting Drugs
| Drug Name | Approval Year | Indications | Mechanism |
| Gefitinib (Iressa) | 2003 | NSCLC (EGFR-mutant) | 1st-gen EGFR TKI, ATP-competitive |
| Erlotinib (Tarceva) | 2004 | NSCLC, pancreatic cancer | 1st-gen EGFR TKI |
| Afatinib (Gilotrif) | 2013 | NSCLC (EGFR exon 19/21 mutations) | 2nd-gen irreversible EGFR/HER2 TKI |
| Osimertinib (Tagrisso) | 2015 | NSCLC (T790M mutation) | 3rd-gen EGFR TKI, targets resistance mutations |
| Cetuximab (Erbitux) | 2004 | Colorectal cancer, head and neck SCC | Monoclonal antibody blocking EGFR |
| Panitumumab (Vectibix) | 2006 | Metastatic colorectal cancer (KRAS wild-type) | Fully human anti-EGFR antibody |
| Necitumumab (Portrazza) | 2015 | Squamous NSCLC | Anti-EGFR monoclonal antibody |
| Dacomitinib (Vizimpro) | 2018 | NSCLC (EGFR-mutant) | 2nd-gen irreversible EGFR TKI |
| Amivantamab (Rybrevant) | 2021 | NSCLC (EGFR exon 20 insertion) | Bispecific EGFR-MET antibody |
EGFR-targeted therapies continue to evolve, with next-generation inhibitors and combination regimens showing promise for overcoming resistance and improving survival outcomes.