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/overexpression.
authors.affiliation: Departments of Medical Oncology and Molecular Pathology, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Eichhorn
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.forename: José
authors.initials: J
authors.lastname: Jiménez
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.forename: Marta
authors.initials: M
authors.lastname: Guzmán
authors.forename: Magui
authors.initials: M
authors.lastname: Gili
authors.forename: Olga
authors.initials: O
authors.lastname: Rodríguez
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodríguez
authors.forename: José
authors.initials: J
authors.lastname: Pérez
authors.forename: Simon R
authors.initials: SR
authors.lastname: Green
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D015513:Oncogene Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C475820:CCNE1 protein, human; C495894:CDK2 protein, human