Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells.
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.
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03766, USA.
Bernardo
B
Orr
Institute for Research in Immunology and Cancer, Université de Montréal, Québec H3T 1J4, Canada.
Lama
L
Talje
Institute for Research in Immunology and Cancer, Université de Montréal, Québec H3T 1J4, Canada.
Zhexian
Z
Liu
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: benjamin.kwok@umontreal.ca.
Benjamin H
BH
Kwok
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: duane.a.compton@dartmouth.edu.
Duane A
DA
Compton
D000970:Antineoplastic Agents / Q000494:pharmacology*; D064107:Aurora Kinase B / Q000378:metabolism; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000187:drug effects*; D002877:Chromosomes, Human / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; C091489:KIF2C protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D016547:Kinesins
Aurora kinase; MCAK; chromosomal instability; drug resistance; mitosis