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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Robichaux JP,Elamin YY,Vijayan RSK,Nilsson MB,Hu L,He J,Zhang F,Pisegna M,Poteete A,Sun H,Li S,Chen T,Han H,Negrao MV,Ahnert JR,Diao L,Wang J,Le X,Meric-Bernstam F,Routbort M,Roeck B,Yang Z,Raymond VM,Lanmandoi
10.1016/j.ccell.2019.09.001subject
Has Abstractpub_date
2019-10-14 00:00:00pages
444-457.e7issue
4eissn
1535-6108issn
1878-3686pii
S1535-6108(19)30384-8journal_volume
36pub_type
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