The YVMA insertion is highlighted in pink, and the P-loop is highlighted in red. j, 3D modeling of HER2 A775insYVMA (blue) and HER2-WT (yellow). Shifts of the P-loop (red arrow) and the α-C helix (blue arrow) into the binding pocket result in steric hindrance, reducing the size of the binding pocket. The NPG insertion is highlighted in pink the P-loop is highlighted in red. i, 3D modeling of EGFR D770insNPG (green) and EGFR T790M (yellow). of the six cell lines is plotted for each concentration ( n = 3 biologically independent experiments). c– h, Averaged dose response curves of cell viability of Ba/F3 cell lines expressing six different EGFR ( c– e) and six different HER2 ( f– h) exon 20 insertion mutations indicated in bold in b treated with first-, second-, or third-generation TKIs for 72 h. b, Schematic of EGFR and HER2 exon 20 insertions generated in a stable Ba/F3 model. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.Ī, PFS of patients with classical EGFR mutations and exon 20 insertion mutations in EGFR demonstrating resistance to first-line therapy (log-rank P < 1.0 × 10 −9). In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy.
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