Somatic mutations in epidermal growth factor receptor (EGFR) kinase domain have been associated with the development of non-small cell lung cancers (NSCLCs), a leading cause of cancer death worldwide. In-frame insertions in exon 20 is the third most common type of EGFR mutations, accounting for 4 to 10% of all EGFR-mutation lung cancers. However, patients with exon 20 insertions still have poor response rate (&lt;5%) to any marketing EGFR-TKI. The mechanisms of exon 20 insertion <i>de novo</i> resistances remain elusive to date. In this study, to elucidate the structural and energetic properties of exon 20 insertion mutations, five exon 20 insertion mutants of highest clinical prevalence (V769_D770insASV, D770_N771insSVD, H773_V774insNPH, A763_Y764insFQEA and V774_C775insHV) were analyzed with different generations of EGFR-TKIs based on molecular dynamics (MD) simulation. According to our designed protocol for structural analysis of both apo protein and drug-protein complex of exon 20 insertion mutations, most of known interaction properties were confirmed in our simulation. Different new mechanisms between exon 20 EGFR mutants and EGFR-TKIs were also discussed and concluded in this study. The provided new structural signatures can help for developing suitable EGFR-TKIs for patients with exon 20 insertions in the future

Computationally predicted signatures of EGFR exon 20 insertions in non small cell lung cancer and its response to irreversible inhibitors

253rd National Meeting (2017)

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