Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18-25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.

Keywords: EGFR; Kinase inhibitor; Lung cancer; Signal transduction; Targeted therapy.

Fig. 1

Pie chart showing the frequencies of EGFR mutations in NSCLC. Data was acquired from COSMIC databases. Data was filtered to contain only mutations from adenocarcinoma. The common resistance mutations T790M and C797S were filtered out.

Fig. 2

Lollipop plot showing the position of EGFR mutations and structural features of EGFR. Orange boxes indicate point mutations, blue boxes indicate insertion/deletion mutations.

Fig. 3

Cartoon showing the structure of the EGFR kinase domain in the active and inactive conformation. In the left panel the inactive conformation is shown, and important residues and structural features are labelled. In the right panel the active conformation is shown, and the approximate location of mutations reported in NSCLC are labelled. Dashed lines indicate salt-bridge interactions.