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

   

Authors:	Scaltriti, M.; Eichhorn, P. J.; Cortes, J.; Prudkin, L.; Aurac, C.; Jimenez, J.; Chandarlapaty, S.; Serra, V.; Prat, A.; Ibrahim, Y. H.; Guzman, M.; Gili, M.; Rodriguez, O.; Rodriguez, S.; Pérez, J.; Green, S. R.; Mai, S.; Rosen, N.; Hudis, C.; Baselga, J.
Article Title:	Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients
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.
Keywords:	clinical article; human cell; antigen expression; cell proliferation; gene overexpression; apoptosis; breast cancer; gene amplification; models, biological; epidermal growth factor receptor 2; tumor xenograft; drug resistance; drug resistance, neoplasm; cell line, tumor; breast neoplasms; protein kinase inhibitors; antibodies, monoclonal; cancer cell; oncogene proteins; gene repression; receptor, erbb-2; tumor growth; trastuzumab; genomic dna; concentration response; cyclin e; copy number variation; cyclin dependent kinase 2; cyclin-dependent kinase 2; cyclin dependent kinase 2 inhibitor
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	108
Issue:	9
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2011-03-01
Start Page:	3761
End Page:	3766
Language:	English
DOI:	10.1073/pnas.1014835108
PUBMED:	21321214
PROVIDER:	scopus
PMCID:	PMC3048107
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79952741351&partnerID=40&md5=7abdf7f68a11f23fa59d3ee6223e0d8f
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 23 June 2011" - "CODEN: PNASA" - "Source: Scopus"

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