HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
作者： Ken Takezawa , Valentina Pirazzoli , Maria E. Arcila , Caroline A. Nebhan , Xiaoling Song
DOI: 10.1158/2159-8290.CD-12-0108
关键词: Erlotinib Hydrochloride 、 Monoclonal 、 Cetuximab 、 Afatinib 、 Drug resistance 、 Cancer research 、 Molecular biology 、 Gene knockdown 、 Biology 、 Adenocarcinoma 、 Rociletinib
摘要: EGFR-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKIs). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models human patients. Since is also a potent HER2 inhibitor, we investigated the role tumor cells. We show vitro vivo that plus significantly inhibits phosphorylation. overexpression or knockdown confers sensitivity, respectively, all studied cell line models. Fluorescent situ hybridization analysis revealed was amplified 12% tumors versus only 1% untreated adenocarcinomas. Notably, amplification T790M were mutually exclusive. Collectively, these results reveal previously unrecognized mechanism TKIs provide rationale assess status possibly target mutant TKIs.
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