Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.

ABSTRACT: Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these

SUBMITTER: Kosaka T 

PROVIDER: S-EPMC5596996 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature