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

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

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

Cancer Cell. 2019 Sep 27;:

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, Vailati Negrao M, Ahnert JR, Diao L, Wang J, Le X, Meric-Bernstam F, Routbort M, Roeck B, Yang Z, Raymond VM, Lanman RB, Frampton GM, Miller VA, Schrock AB, Albacker LA, Wong KK, Cross JB, Heymach JV

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.

PMID: 31588020 [PubMed - as supplied by publisher]