J. Robichaux, Y. Elamin, R. Vijayan, M. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, M. Pisegna, A. Poteete, Huiying Sun, S. Li, Ting Chen, Han Han, M. Vailati Negrao, J. R. Ahnert, L. Diao, Jing Wang, X. Le, F. Meric-Bernstam, M. Routbort, B. Roeck, Zane Yang, V. Raymond, R. Lanman, G. Frampton, V. Miller, A. Schrock, L. Albacker, Kwok-Kin Wong, J. Cross, J. Heymach
Cancer cell, 2019
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.
Cited by 36 publications.
Field of study: Medicine