Abstract 22: Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer
Bibliographic record
Abstract
Abstract HER2 amplification/overexpression occurs in 20% of breast cancers and is associated with poor prognosis. Therapeutic agents against HER2, including monoclonal antibodies and tyrosine kinase inhibitors, have shown to improve the survival of these patients. However, primary and acquired resistance to these agents is a major barrier to the effective treatment of this disease. Aiming to identify the molecular pathways responsible for resistance to anti-HER2 therapy we have established HER2 positive breast cancer cell lines refractory to the anti-proliferative effects of the therapeutic antibody trastuzumab. We have studied their acquired genetic aberrations by performing gene expression microarray and genome single nucleotide polymorphisms analyses. In trastuzumab resistant cells we identified an increase in copy number variation in locus 19q12. This chromosome region comprises seven genes, among them cyclin E1 (CCNE1). We further confirmed Cyclin E over-expression in trastuzumab resistant cells by western blot. To test the hypothesis that increased cyclin E expression could play a role in the acquisition of trastuzumab resistance we have demonstrated that ablation of cyclin E expression by siRNA restores trastuzumab sensitivity in HER2 positive resistant cells. Furthermore, we have determined that trastuzumab resistant cells are highly sensitive to the specific CDK inhibitor seliciclib and its more potent derivative Cmpd. 5 (Cyclacel) both in vitro and in vivo. In addition, we have analyzed a cohort of HER2 positive breast cancer patients treated with trastuzumab-based therapy and identified a proportion of patients refractory to trastuzumab that harbor amplification of the cyclin E gene. Our results suggest that cyclin E amplification decreases trastuzumab sensitivity and may provide the rationale to test the efficacy of CDK2 inhibitors in breast cancer patients with cyclin E amplification that escaped trastuzumab therapy. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 22.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".