RRC ID 58088
Author 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 RB, Frampton GM, Miller VA, Schrock AB, Albacker LA, Wong KK, Cross JB, Heymach JV.
Title Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.
Journal Cancer Cell
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.
Volume 36(4)
Pages 444-457.e7
Published 2019-10-14
DOI 10.1016/j.ccell.2019.09.001
PII S1535-6108(19)30384-8
PMID 31588020
PMC PMC6944069
MeSH Ado-Trastuzumab Emtansine / pharmacology* Ado-Trastuzumab Emtansine / therapeutic use Adult Animals Antineoplastic Agents, Immunological / pharmacology Antineoplastic Agents, Immunological / therapeutic use Antineoplastic Combined Chemotherapy Protocols / pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use DNA Mutational Analysis Datasets as Topic Disease Models, Animal Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Drug Synergism Female Humans Male Mice Mice, Transgenic Mutation Neoplasms / drug therapy* Neoplasms / genetics Neoplasms / mortality Neoplasms / pathology Progression-Free Survival Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Quinazolines / pharmacology* Quinazolines / therapeutic use Receptor, ErbB-2 / antagonists & inhibitors* Receptor, ErbB-2 / genetics
IF 26.602
Times Cited 15
Resource
Human and Animal Cells CW-2(RCB0778)