CENP-E Inhibition Induces Chromosomal Instability and Synergizes with Diverse Microtubule-Targeting Agents in Breast Cancer.

Autor:	Tucker JB; Cancer Biology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin., Carlsen CL; Cellular and Molecular Biology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin., Scribano CM; Cellular and Molecular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, Wisconsin., Pattaswamy SM; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Burkard ME; Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin., Weaver BA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.; Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Aug 15; Vol. 84 (16), pp. 2674-2689.
DOI:	10.1158/0008-5472.CAN-23-3332
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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