Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America.
Cancer Biology Graduate Training Program, University of Wisconsin, Madison, Wisconsin, United States of America.
PLoS Biol. 2023 Oct 26;21(10):e3002339. doi: 10.1371/journal.pbio.3002339. eCollection 2023 Oct.
Microtubule-targeted agents are commonly used for cancer treatment, though many patients do not benefit. Microtubule-targeted drugs were assumed to elicit anticancer activity via mitotic arrest because they cause cell death following mitotic arrest in cell culture. However, we recently demonstrated that intratumoral paclitaxel concentrations are insufficient to induce mitotic arrest and rather induce chromosomal instability (CIN) via multipolar mitotic spindles. Here, we show in metastatic breast cancer and relevant human cellular models that this mechanism is conserved among clinically useful microtubule poisons. While multipolar divisions typically produce inviable progeny, multipolar spindles can be focused into near-normal bipolar spindles at any stage of mitosis. Using a novel method to quantify the rate of CIN, we demonstrate that cell death positively correlates with net loss of DNA. Spindle focusing decreases CIN and causes resistance to diverse microtubule poisons, which can be counteracted by addition of a drug that increases CIN without affecting spindle polarity. These results demonstrate conserved mechanisms of action and resistance for diverse microtubule-targeted agents. Trial registration: clinicaltrials.gov, NCT03393741.
微管靶向药物通常用于癌症治疗,但许多患者并未从中获益。微管靶向药物被认为通过有丝分裂阻滞发挥抗癌活性,因为它们在细胞培养中导致有丝分裂阻滞后引起细胞死亡。然而,我们最近证明,肿瘤内紫杉醇浓度不足以诱导有丝分裂阻滞,而是通过多极有丝分裂纺锤体诱导染色体不稳定性(CIN)。在这里,我们在转移性乳腺癌和相关的人类细胞模型中表明,这种机制在临床上有用的微管毒素中是保守的。虽然多极分裂通常产生无法存活的后代,但多极纺锤体可以在有丝分裂的任何阶段聚焦成近乎正常的双极纺锤体。使用一种新的方法来量化 CIN 的速率,我们证明细胞死亡与 DNA 的净丢失呈正相关。纺锤体聚焦可降低 CIN 并引起对多种微管毒素的耐药性,通过添加一种不影响纺锤体极性但增加 CIN 的药物可以逆转这种耐药性。这些结果表明,不同的微管靶向药物具有保守的作用机制和耐药性。试验注册:clinicaltrials.gov,NCT03393741。