破解三阴性乳腺癌紫杉醇疗效盲盒
紫杉醇（泰素）是用来治疗乳腺癌等多种恶性肿瘤的细胞毒性化疗药物，尤其对于主要依靠化疗的三阴性乳腺癌。不过，紫杉醇的疗效如同盲盒，并非全部患者都能获益，其细胞毒性机制亦未完全明确。
2021年9月8日，美国科学促进会《科学》旗下《转化医学》在线发表威斯康星大学麦迪逊总校的研究报告，探讨了紫杉醇对乳腺肿瘤的细胞毒性机制及其疗效预测指标。
该研究发现，乳腺癌患者肿瘤内紫杉醇浓度并不足以诱导肿瘤细胞有丝分裂停滞。相反，紫杉醇临床治疗浓度可诱导人类三阴性乳腺癌Cal51、MDA-MB-231细胞多极有丝分裂纺锤体形成。不过，早期多极化程度并不能预测紫杉醇对患者的疗效。多极分裂常常引起细胞死亡，而多极纺锤体在分裂之前或多或少地集中形成双极纺锤体，并且在整个有丝分裂过程中保持多极对于诱导紫杉醇引起细胞死亡所需的染色体高度不稳定性至关重要。紫杉醇可增加多极分裂，导致细胞毒性提高。相反，减少紫杉醇诱导的多极分裂可降低紫杉醇疗效。
此外，该研究发现已经存在的染色体不稳定性可使乳腺癌细胞对紫杉醇敏感，诱导染色体不稳定性的基因技术和药物都可提高紫杉醇疗效。晚期乳腺癌患者接受紫杉类治疗前的染色体不稳定性与紫杉类疗效成正比，故紫杉类治疗前染色体不稳定性较高的患者对紫杉类疗效显著较好。
因此，该研究结果表明，紫杉醇通过增加细胞分裂时的染色体错误分离而产生细胞毒性，紫杉醇治疗前的染色体不稳定性可以作为预测紫杉醇疗效的生物学标志。此外，在整个有丝分裂过程中增加染色体不稳定性或维持多极纺锤体的药物可显著提高紫杉醇临床疗效。
Sci Transl Med. 2021 Sep 8;13(610):eabd4811.
Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel.
Christina M. Scribano, Jun Wan, Karla Esbona, John B. Tucker, Amber Lasek, Amber S. Zhou, Lauren M. Zasadil, Ryan Molini, Jonathan Fitzgerald, Angela M. Lager, Jennifer J. Laffin, Kayla Correia-Staudt, Kari B. Wisinski, Amye J. Tevaarwerk, Ruth O'Regan, Stephanie M. McGregor, Amy M. Fowler, Richard J. Chappell, Tim S. Bugni, Mark E. Burkard, Beth A. Weaver.
University of Wisconsin-Madison, Madison, WI, USA; Wisconsin State Laboratory of Hygiene, Madison, WI, USA.
Unpacking paclitaxel response: Paclitaxel is a common treatment for many cancers, although not all patients benefit from the treatment and the mechanism by which it works is unclear. Here, Scribano et al. studied patients with breast cancer undergoing paclitaxel treatment as part of a clinical trial to elucidate the drug's mechanism of action, demonstrating that paclitaxel treatment increased cell division with chromosome missegregation to induce cytotoxicity. They also found that increased chromosomal instability in tumor cells before treatment was predictive of response to taxane therapy. Although the findings require further validation, this increased chromosomal instability may serve as a predictive biomarker for paclitaxel response in patients with breast cancer.
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.
DOI: 10.1126/scitranslmed.abd4811