Abstract 1844: Centriole amplification sensitizes cells to paclitaxel

Abstract

Abstract Paclitaxel (Taxol) is a widely utilized treatment for primary and metastatic breast cancer. However, only about 50% of patients respond and no predictive biomarker for paclitaxel efficacy is currently available. Identification of a clinically validated predictive biomarker would substantially improve patient outcomes. Aneuploidy, an aberrant chromosome number, was recognized in the late 1800s as a hallmark of tumor cells. This led to the hypothesis that aneuploidy drives tumorigenesis. However, experiments in animal models have shown that the effect of aneuploidy on tumors depends on the rate of ongoing chromosome missegregation, also known as chromosomal instability (CIN). Low rates of CIN are weakly tumor promoting, while high rates of CIN lead to cell death and tumor suppression due to loss of one or more essential chromosomes. Combining two independent insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We have recently shown that, in primary breast cancer patients, paclitaxel does not reach sufficiently high concentrations to cause mitotic arrest, as it does at typically used concentrations in cell culture. Instead, low clinically relevant doses of paclitaxel cause CIN due to multipolar spindles. We hypothesize that a preexisting low rate of chromosomal instability (CIN), which occurs in about 50% of breast tumors, sensitizes cells to paclitaxel treatment, since paclitaxel increases their rate of CIN over a maximally tolerated threshold. Centrosome amplification is common in breast cancer and can cause CIN through induction of multipolar spindles. To test whether CIN induced by centrosome amplification sensitizes cells to low, clinically relevant doses of paclitaxel, we inducibly overexpressed Polo-like kinase 4 (Plk4), the master regulator of centriole duplication, to generate supernumerary centrioles. Plk4 overexpression induced centriole amplification and increased the incidence of multipolar divisions, even in subclinical levels of paclitaxel. Consistent with our hypothesis, CIN induced by supernumerary centrosomes potentiates the decrease in cell viability caused by paclitaxel treatment. Decreased cell viability is accompanied by an increase in mitotic errors, CIN, and cell death and a reduction in the percentage of cycling cells. This data suggests that the subset of patients whose tumors exhibit centrosome amplification prior to treatment may be more likely to benefit from paclitaxel therapy. Citation Format: Amber L. Lasek, Eric M. Britigan, Beth A. Weaver. Centriole amplification sensitizes cells to paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1844.