2. Academic Validation
  3. Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells

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

  • Cell Rep. 2016 Nov 8;17(7):1755-1763. doi: 10.1016/j.celrep.2016.10.030.
Bernardo Orr 1,  Lama Talje 2,  Zhexian Liu 2,  Benjamin H Kwok 3,  Duane A Compton 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03766, USA.
  • 2 Institute for Research in Immunology and Cancer, Université de Montréal, Québec H3T 1J4, Canada.
  • 3 Institute for Research in Immunology and Cancer, Université de Montréal, Québec H3T 1J4, Canada; Département de Médecine, Université de Montréal, Québec H3T 1J4, Canada. Electronic address: [email protected].
  • 4 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03766, USA. Electronic address: [email protected].
PMID: 27829147 DOI: 10.1016/j.celrep.2016.10.030
Abstract

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.

Keywords

Aurora kinase; MCAK; chromosomal instability; drug resistance; mitosis.

Figures
Products