Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer

Abstract

Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor (EGFR) gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis. Here, we review the developments over the last 5 years in which pre-clinical studies, including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase, have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these EGFR mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit EGFR exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.

Fig. 1

Developments in understanding EGFR exon 20 insertion-positive NSCLC. A timeline of key clinical and pre-clinical studies that have established the response of EGFR exon 20 insertion NSCLC to EGFR inhibitors and recent progress towards the development of novel therapeutic strategies for this molecular subtype

Fig. 2

EGFR Exon 20 insertion mutations in NSCLC. Within NSCLC, all EGFR mutations are clustered across exons 18–22 which encode the tyrosine kinase domain. In particular, 4–10% of EGFR mutations are heterogeneous in-frame insertions of between 1–7 amino acids (indicated as ins X) across a span of ~15 amino acids (D761–C775) in exon 20. The prevalence of exon 20 insertions that occur at different amino acid positions are shown by the red bars. Mutations occur within the C-terminal end of the C-helix or more frequently in the loop that immediately follows. Mutation frequency distribution was calculated using COSMIC v86 (http://cancer.sanger.ac.uk) after filtering for NSCLC adenocarcinomas harboring exon 20 insertions (n = 349)

Fig. 3

Impact of deletions and insertions on EGFR activation. Upon ligand-binding, the regulatory C-helix pivots from an outward, inactive conformation to an inward, active conformation to form key interactions with the p-loop of the active site located in the cleft between the N-lobe and C-lobe. Oncogenic mutations such as exon 19 deletions can “pull” the C-helix from the N-terminal side whilst exon 20 insertions “push” from the C-terminal side to stabilize the active state of EGFR even in the absence of ligand