Drugs that perturb microtubules are commonly used to treat breast cancers of all subtypes in both early stage and metastatic disease, but they are effective in only approximately 50% of patients. High concentrations of microtubule-targeting agents can elicit mitotic arrest in cell culture models; however, recent evidence from primary and metastatic breast cancers has revealed that these agents only accumulate at intratumoral levels capable of inducing abnormal multipolar mitotic spindles, not mitotic arrest. Although the maintenance of multipolar spindles can generate cytotoxic rates of chromosomal instability (CIN), focusing of aberrant multipolar spindles into normal bipolar spindles can dramatically reduce CIN and confer resistance to microtubule poisons. Here, we showed that inhibition of the mitotic kinesin centromeric-associated protein-E (CENP-E) overcomes resistance caused by focusing multipolar spindles. Clinically relevant microtubule-targeting agents used a mechanistically conserved pathway to induce multipolar spindles without requiring centrosome amplification. Focusing could occur at any point in mitosis, with earlier focusing conferring greater resistance to antimicrotubule agents. CENP-E inhibition increased CIN on focused spindles by generating chromosomes that remained misaligned at spindle poles during anaphase, which substantially increased death in the resulting daughter cells. CENP-E inhibition synergized with diverse, clinically relevant microtubule poisons to potentiate cell death in cell lines and suppress tumor growth in orthotopic tumor models. These results suggest that primary resistance to microtubule-targeting drugs can be overcome by simultaneous inhibition of CENP-E. Significance: The increased incidence of polar chromosomes induced by inhibition of the mitotic kinesin CENP-E exacerbates chromosomal instability, reduces daughter cell viability, and improves sensitivity to microtubule-targeting therapies.

中文翻译：

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CENP-E 抑制诱导染色体不稳定，并与乳腺癌中的多种微管靶向剂协同作用。


扰乱微管的药物通常用于治疗早期和转移性疾病中所有亚型的乳腺癌，但它们仅对大约 50% 的患者有效。高浓度的微管靶向试剂可在细胞培养模型中引发有丝分裂停滞;然而，来自原发性和转移性乳腺癌的最新证据表明，这些药物仅在能够诱导异常多极有丝分裂纺锤体的瘤内水平积累，而不是有丝分裂停滞。尽管多极纺锤体的维持会产生染色体不稳定性 （CIN） 的细胞毒率，但将异常的多极纺锤体聚焦到正常的双极纺锤体中可以显着降低 CIN 并赋予对微管毒物的抵抗力。在这里，我们表明有丝分裂驱动蛋白着丝粒相关蛋白-E （CENP-E） 的抑制克服了聚焦多极纺锤体引起的阻力。临床相关的微管靶向药物使用机械上保守的途径来诱导多极纺锤体，而无需中心体扩增。聚焦可能发生在有丝分裂的任何一点，较早聚焦对抗微管药物具有更大的抵抗力。CENP-E 抑制通过产生在后期在纺锤体极处保持错位的染色体来增加聚焦纺锤体上的 CIN，这大大增加了所得子细胞的死亡。CENP-E 抑制与多种临床相关的微管毒物协同作用，以增强细胞系中的细胞死亡并抑制原位肿瘤模型中的肿瘤生长。这些结果表明，通过同时抑制 CENP-E 可以克服对微管靶向药物的原发性耐药。 意义： 抑制有丝分裂驱动蛋白 CENP-E 诱导的极性染色体发生率增加加剧了染色体不稳定，降低了子细胞活力，并提高了对微管靶向治疗的敏感性。