EGFR AND ITS DYSREGULATION IN NSCLC
EGFR mutations (EGFRm) impair the function of EGFR and are the second most common oncogenic driver in NSCLC – but not all are EGFR-TKI-sensitive[1][2]
Wild-type (or normal) EGFR is a cell surface protein that regulates many cell processes[3]
Wild-type (or normal) epidermal growth factor receptor (EGFR) is a cell surface protein that regulates many cell processes.[3] EGFR is a tyrosine kinase receptor member of the ERBB family that regulates signalling pathways that control cell growth, motility, and survival (fig. 1).[3]
Figure 1. Endogenous functions of active wild-type EGFR
When active, EGFR is involved in the regulation of several cell processes, including cell proliferation, survival, and migration[2][4][5]
EGFR is encoded by the exons of the EGFR gene, located on chromosome 7 at position 12.[3]
The EGFR protein exists in an inactive state.[2] Ligand binding to the extracellular portion of the receptor leads to receptor activation (fig. 2).[2] This leads to receptor homo-dimerisation (where two EGFR monomers join together) or hetero-dimerisation (where one EGFR monomer joins with a different dimerisation partner).[3] Following this, ATP can bind to the tyrosine kinase domain on the cytoplasmic side of EGFR, leading to the phosphorylation of the receptor, and activation of downstream signalling through pathways such as the PI3K/AKT/mTOR and RAS/RAF/ MAPK pathways (fig. 2).[3]
Figure 2. Activation of wild-type EGFR by ligand binding
Inactive conformation: in the absence of a ligand, the EGFR receptor is inactive. The ATP binding pocket is blocked by the C-helix protein.[2]
Active conformation: ligand binding to the extracellular portion of the receptor leads to a conformational change. The C-helix pivots from an “outward” inactive conformation to an “inward”, active conformation, exposing the ATP binding pocket.[2]
Adapted from Ferguson KM et al. 2003, and Vyse S, Huang PH. 2019.[2][6]
The constitutive activation of EGFR signalling, via a mutation in EGFR or one of its downstream signalling components (e.g. KRAS), can lead to excess proliferation, survival, and migration – driving NSCLC.[3]
If a patient’s tumour has no detectable EGFR mutation (wild-type or EGFR mutation-negative), then test for a different driver mutation (e.g. ALK mutation) to help guide treatment.[7]
Find out more about different genetic mutations in NSCLC, and their use as molecular biomarkers.
EGFR gene alterations play a critical role in driving NSCLC[8]
Dysregulated EGFR drives NSCLC – excess signalling can result in cell proliferation, angiogenesis, invasion, and metastasis.[8]
There are two circumstances in which abnormal EGFR can drive excess signalling:
EGFR over-expression – observed in 40–89% of all NSCLCs, and is associated with a poor prognosis.[3][8]
EGFR mutations (EGFRm) – observed in ~13% of all NSCLCs in Europe, though this figure is reported to be higher in Asia (~49%).[9]
Many EGFR mutations result in the constitutive activation of EGFR (where the receptor is always switched “on”), even in the absence of a binding ligand, which drives tumour growth and survival.[3] EGFR mutations found in NSCLC include – but are not limited to – deletions in exon 19, substitution/point mutations (Exon 21 L858R, Exon 20 T790M), and EGFR exon 20 insertion mutations.[1]
Currently approved EGFR-TKIs are not effective against EGFR exon 20 insertion mutations – these mutations generally have primary intrinsic resistance to EGFR-TKIs.[2][10]
Discover more about EGFR mutations in NSCLC.
Discover more about EGFR exon 20 insertion mutations here:
ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR-tyrosine kinase inhibitor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NSCLC, non-small cell lung cancer; PI3K, phosphatidylinositol 3-kinase.
CP-223640
