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Edited by Carlos L. Arteaga, Vanderbilt University School of Medicine, Nashville, TN, and accepted by the Editorial Board January 28, 2011 (received for review October 25, 2010)
↵1M.S. and P.J.E. contributed equally to this work.
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/overexpression.
Footnotes
- 2To whom correspondence should be addressed. E-mail: jbaselga{at}partners.org.
Author contributions: M.S., P.J.E., and J.B. designed research; M.S., P.J.E., J.C., L.P., C.A., J.J., V.S., A.P., Y.H.I., M. Guzmán, M. Gili, O.R., and S.R. performed research; S.R.G. and S.M. contributed new reagents/analytic tools; M.S., P.J.E., J.C., L.P., C.A., J.J., S.C., V.S., A.P., Y.H.I., J.P., N.R., C.H., and J.B. analyzed data; and M.S., P.J.E., and J.B. wrote the paper.
Conflict of interest statement: S.R.G. is an employee of Cyclacel, Ltd.
This article is a PNAS Direct Submission. C.L.A. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1014835108/-/DCSupplemental.
Freely available online through the PNAS open access option.
Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients
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