Abstract 1750: Clinically relevant paclitaxel concentrations cause chromosome missegregation rather than mitotic arrest.

Abstract

Abstract Paclitaxel is a chemotherapeutic, microtubule-stabilizing drug used to treat a variety of cancers, including those of the breast. In the neoadjuvant setting, paclitaxel effects tumor shrinkage in up to half of patients. Identification of a biomarker to predict response to paclitaxel would reduce side effects and improve patient outcomes. It has long been known that micromolar concentrations of paclitaxel cause cells in culture to arrest in mitosis, which can lead to cell death. However, the concentration range found within patient tumors remains unclear, both because it has not been directly measured and because paclitaxel accumulates intracellularly up to 1000 fold. In a pilot clinical trial, we are directly measuring the intratumoral drug concentration in breast tumors following neoadjuvant paclitaxel treatment. Our preliminary data support the hypothesis that treatment of cultured cells with a low nanomolar concentration more accurately models the intratumoral drug levels in breast cancer patients. Unlike treatment with micromolar concentrations, treatment with low nanomolar paclitaxel does not cause a significant mitotic arrest. Rather, cells treated with low nanomolar paclitaxel frequently proceed through mitosis with multipolar mitotic spindles, resulting in chromosome missegregation and the production of two or more daughter cells. This alternative mechanism of action may explain why tumors treated with paclitaxel fail to show an increase in mitotic index. Previous studies have shown that low rates of chromosome missegregation are well tolerated, but high rates of chromosome missegregation cause cell death due to loss of both copies of one or more essential chromosomes. Therefore, the fidelity of chromosome segregation may be of use as a predictor of response to paclitaxel. In chromosomally stable breast cancer cells, exposure to paclitaxel for two days is sufficient to induce aneuploidy, and within three days there is an increase in cell death. However, a subset of cells are able to survive in low nM paclitaxel for over one week, and survival is higher than in cells which exhibit chromosomal instability (CIN), and have a preexisting rate of chromosome missegregation during division. In patients, chromosomal stability is of potential use as a predictive biomarker to select patients most likely to respond to paclitaxel treatment. Citation Format: Lauren M. Zasadil, Mark Burkard, Beth A. Weaver. Clinically relevant paclitaxel concentrations cause chromosome missegregation rather than mitotic arrest. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2013-1750