Journal
NATURE MEDICINE
Volume 24, Issue 5, Pages 638-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0007-9
Keywords
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Funding
- Lung SPORE grant [P50 CA070907, P50 CA196530]
- Lung Cancer Research Fund
- NIH [R01 CA190628]
- NIH Cancer Center Support Grant [P30 CA016672]
- Rexanna Foundation for Fighting Lung Cancer
- Exon 20 Group
- University of Texas MD Anderson Cancer Center Bruton Endowed Chair in Tumor Biology
- Stading Fund for EGFR inhibitor resistance
- Hallman fund
- Fox Lung EGFR Inhibitor Fund
- Christine J. Burge Endowment for Lung Cancer Research at the University of Colorado Cancer Center
- Burge family
- Miramont Cares foundation
- Italian Association for Cancer Research
- Cancer Prevention Research Institute of Texas [DP150086]
- National Science Foundation [CHE-1411859]
- National Institute of General Medical Sciences [GM070737]
- Spectrum Pharmaceutical
- NATIONAL CANCER INSTITUTE [P50CA196530, P30CA016672, P50CA070907, R01CA190628, R01CA140594, P50CA058187, R01CA166480] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM070737] Funding Source: NIH RePORTER
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Although 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. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. 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. 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. 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%. 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.
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