EGFR-TKIs interact with the ATP-binding pocket of EGFR’s tyrosine kinase domain. They function as competitive inhibitors of ATP.
Mutations in the ATP binding pocket (exons 18–21) therefore have the potential to alter the binding affinity of EGFR not only for ATP but also for EGFR-TKIs – meaning different EGFR mutations have different levels of sensitivity to treatment with EGFR-TKIs (fig. 3).
Figure 3. Deletions, substitutions/point mutations, and insertions activate EGFR even in the absence of a ligand, changing the shape of the EGFR-TKI binding pocket and ultimately impacting interactions with EGFR-TKIs
Exon 19 deletions occur close to the N-terminal side. They shorten the protein and “pull” the C-helix, exposing the ATP-binding pocket – the site of interaction with EGFR-TKIs.
Substitution/point mutations destabilise the inactive form of EGFR and can cause conformational changes that expose the ATP-binding pocket – the site of interaction with EGFR-TKIs.
Exon 20 insertion mutations add an extra portion of protein near the C-terminal side, “pushing” the C-helix. These mutations are generally insensitive to treatment with EGFR-TKIs due to steric hindrance at the EGFR-TKI binding site.
Adapted from Ferguson KM et al. 2003, and Vyse S, Huang PH. 2019.
Data have suggested that a third-generation EGFR-TKI may demonstrate clinical activity in some patients who have EGFRm ex20ins NSCLC, though this requires further evaluation.
Watch an expert review on EGFR in NSCLC with Matthew Krebs (UK), Antonio Passaro (Italy), Joshua Bauml (USA), and Luis Paz-Ares (Spain), on our Janssen Oncology medical education resource
ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; EGFRm, mutated EGFR; EGFR-TKI, EGFR-tyrosine kinase inhibitor; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer.