| Literature DB >> 31588020 |
Jacqulyne P Robichaux1, Yasir Y Elamin1, R S K Vijayan2, Monique B Nilsson1, Lemei Hu1, Junqin He1, Fahao Zhang1, Marlese Pisegna1, Alissa Poteete1, Huiying Sun1, Shuai Li3, Ting Chen3, Han Han3, Marcelo Vailati Negrao1, Jordi Rodon Ahnert4, Lixia Diao5, Jing Wang6, Xiuning Le1, Funda Meric-Bernstam4, Mark Routbort6, Brent Roeck7, Zane Yang7, Victoria M Raymond8, Richard B Lanman8, Garrett M Frampton9, Vincent A Miller9, Alexa B Schrock9, Lee A Albacker9, Kwok-Kin Wong3, Jason B Cross2, John V Heymach10.
Abstract
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.Entities:
Keywords: ERBB2 mutant; HER2 mutant; NSCLC; T-DM1; TKI; exon 20; pan-cancer; poziotinib
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Year: 2019 PMID： 31588020 PMCID： PMC6944069 DOI： 10.1016/j.ccell.2019.09.001
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743