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. HER2 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which includes EGFR itself, HER2, HER3, and HER4. Homo-or heterodimerization of these receptors results in phosphorylation of residues in the intracellular domain and consequent recruitment of adapter molecules responsible for the initiation of several signaling pathways involved in cell proliferation and survival (1, 2). Approximately 20% of breast cancers exhibit HER2 gene amplification/overexpression, resulting in an aggressive tumor phenotype and reduced survival (3, 4). Therapy of HER2 + breast cancer with anti-HER2 agents, including monoclonal antibodies and small molecule tyrosine kinase inhibitors, has markedly improved the outcome of this disease (5). Trastuzumab, a recombinant humanized monoclonal antibody that binds to the extracellular domain of HER2, improves survival in patients with HER2 + breast cancer, in both the metastatic (6, 7) and adjuvant settings (8). The overall antitumor activity of trastuzumab is due to a combination of mechanisms, including inhibition of ligandindependent HER2 dimerization (9), HER2 down-regulation (10,11), that lead to disruption of HER2-dependent PI3K/Akt signaling (12) and induction of G1 arrest through stabilization of the CDK inhibitor p27 (13). In addition, trastuzumab also mediates antibod...

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“…Interestingly, inactivation of both cyclin D and CDK4 are capable of inhibiting HER2-mediated tumorigenesis in genetically engineered mouse models, highlighting the importance of this cell cycle pathway in HER2-mediated oncogenesis (45)(46)(47). Recently, it also was observed that amplification or overexpression of cyclin E is a mechanism of trastuzumab resistance (48). These published data on cyclin/ CDK complexes support the concept that a gene, such as PPM1H, that is involved in regulation of p27 could play a role in HER2 signaling and trastuzumab resistance.…”

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