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

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. Tailoring therapies for lung cancer Activating mutations in the epidermal growth factor receptor ( EGFR ) gene are commonly observed in non-small-cell lung cancer (NSCLC). Treatment with EGFR inhibitors has proven successful in many patients harboring such mutations, but patients with EGFR exon 20 insertion mutations do not respond these drugs. Simon Vyse and Paul H Huang at The Institute of Cancer Research in London, UK, review the latest research on the effect that the insertion of three or more nucleotide base pairs into EGFR exon 20 has on the receptor’s structure and activity, which contributes to its poor sensitivity to currently available EGFR inhibitors. Promising preclinical findings with compounds that selectively target the EGFR exon 20 insertion mutant protein may lead to new treatment options for patients with this form of NSCLC.