Journal
CANCER CELL
Volume 36, Issue 4, Pages 444-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.09.001
Keywords
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Funding
- David Bruton, Jr. Endowment
- Rexanna Foundation for Fighting Lung Cancer
- CCSG Lung Cancer Program
- Lung Cancer Moon Shot Program
- Spectrum Pharmaceuticals
- Kopelman Fund for Lung Cancer Research
- Exon 20 Group
- Lung Cancer Research Fund
- Lung SPORE grant [5 P50 CA070907]
- ASCO [CDA-57112]
- Hallman fund
- [R01 CA190628-NIH/NCI]
- [1U54CA224065-01]
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We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
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