Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.

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 Cell

journal_title

Cancer cell

authors

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,Lanman

doi

10.1016/j.ccell.2019.09.001

subject

Has Abstract

pub_date

2019-10-14 00:00:00

pages

444-457.e7

issue

4

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(19)30384-8

journal_volume

36

pub_type

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