Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients

Maurizio Scaltriti, Pieter J. Eichhorn, Javier Cortés, Ludmila Prudkin, Claudia Aurac, José Jiménez, Sarat Chandarlapaty, Violeta Serra, Aleix Prat, Yasir H. Ibrahim, Marta Guzmán, Magui Gili, Olga Rodríguez, Sonia Rodríguez, José Pérez, Simon R. Green, Sabine Mai, Neal Rosen, Clifford Hudis, José Baselga

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197 Citations (Scopus)

Abstract

Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2+ patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/over-expression.
Original languageEnglish
Pages (from-to)3761-3766
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number9
DOIs
Publication statusPublished - 1 Mar 2011

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