Paclitaxel (Taxol) is a cornerstone of cancer treatment. However, its mechanism of cytotoxicity is incompletely understood and not all patients benefit from treatment. We show that patients with breast cancer did not accumulate sufficient intratumoral paclitaxel to induce mitotic arrest in tumor cells. Instead, clinically relevant concentrations induced multipolar mitotic spindle formation. However, the extent of early multipolarity did not predict patient response. Whereas multipolar divisions frequently led to cell death, multipolar spindles focused into bipolar spindles before division at variable frequency, and maintaining multipolarity throughout mitosis was critical to induce the high rates of chromosomal instability necessary for paclitaxel to elicit cell death. Increasing multipolar divisions in paclitaxel resulted in improved cytotoxicity. Conversely, decreasing paclitaxel-induced multipolar divisions reduced paclitaxel efficacy. Moreover, we found that preexisting chromosomal instability sensitized breast cancer cells to paclitaxel. Both genetic and pharmacological methods of inducing chromosomal instability were sufficient to increase paclitaxel efficacy. In patients, the amount of pretreatment chromosomal instability directly correlated with taxane response in metastatic breast cancer such that patients with a higher rate of preexisting chromosomal instability showed improved response to taxanes. Together, these results support the use of baseline rates of chromosomal instability as a predictive biomarker for paclitaxel response. Furthermore, they suggest that agents that increase chromosomal instability or maintain multipolar spindles throughout mitosis will improve the clinical utility of paclitaxel.

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染色体不稳定性使患者乳腺肿瘤对紫杉醇诱导的多极分裂敏感

紫杉醇（紫杉醇）是癌症治疗的基石。然而，其细胞毒性机制尚不完全清楚，并非所有患者都能从治疗中受益。我们发现乳腺癌患者的瘤内紫杉醇没有积累足够的量来诱导肿瘤细胞有丝分裂停滞。相反，临床相关浓度诱导多极有丝分裂纺锤体形成。然而，早期多极化的程度并不能预测患者的反应。虽然多极分裂经常导致细胞死亡，但多极纺锤体在以不同频率分裂之前集中为双极纺锤体，并且在整个有丝分裂过程中维持多极对于诱导紫杉醇引起细胞死亡所需的高染色体不稳定性至关重要。紫杉醇中多极分裂的增加导致细胞毒性的改善。相反，减少紫杉醇诱导的多极分裂会降低紫杉醇的功效。此外，我们发现预先存在的染色体不稳定性使乳腺癌细胞对紫杉醇敏感。诱导染色体不稳定的遗传和药理学方法都足以提高紫杉醇的疗效。在患者中，治疗前染色体不稳定性的程度与转移性乳腺癌中紫杉烷的反应直接相关，因此预先存在染色体不稳定性较高的患者对紫杉烷的反应有所改善。总之，这些结果支持使用染色体不稳定基线率作为紫杉醇反应的预测生物标志物。此外，他们表明增加染色体不稳定性或在有丝分裂过程中维持多极纺锤体的药物将改善紫杉醇的临床效用。