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Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells.

Orr B, Talje L, Liu Z, Kwok BH, Compton DA

Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03766, USA.

Karyotype diversity is a hallmark of solid tumors that contributes to intratumor heterogeneity. This diversity is generated by persistent chromosome mis-segregation associated with chromosomal instability (CIN). CIN correlates with tumor relapse and is thought to promote drug resistance by creating a vast genomic landscape through which karyotypically unique clones survive lethal drug selection. We explore this proposition using a small molecule (UMK57) that suppresses chromosome mis-segregation in CIN cancer cells by potentiating the activity of the kinesin-13 protein MCAK. Sublethal doses of UMK57 destabilize kinetochore-microtubule (k-MT) attachments during mitosis to increase chromosome segregation fidelity. Surprisingly, chromosome mis-segregation rebounds in UMK57-treated cancer cells within a few days. This rapid relapse is driven by alterations in the Aurora B signaling pathway that hyper-stabilize k-MT attachments and is reversible following UMK57 removal. Thus, cancer cells display adaptive resistance to therapies targeting CIN through rapid and reversible changes to mitotic signaling networks.

Cell Rep 2016;17(7):1755-1763.

Pubmed ID: 27829147

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