Molecular Pathways

Anaphase Catastrophe Is a Target for Cancer Therapy

Fabrizio Galimberti1, Sarah L. Thompson2, Saranya Ravi1, Duane A. Compton2,3, and Ethan Dmitrovsky1,3,4

AbstractNeoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can

be exploited to disrupt tumor cell growth, potentially with limited consequences to normal cells.

Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that

increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that

transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor

cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and

promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of

these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter

cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe

specifically kills tumor cells with more than 2 centrosomes. This death program can occur after genetic

or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined

treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras

mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be

pharmacologically induced for apoptotic death of cancer cells and is, therefore, appealing to engage for

cancer therapy and prevention. Clin Cancer Res; 17(6); 1218–22. �2011 AACR.

Background

Anaphase catastrophe is a proapoptotic death mechan-ism observed in cancer cells with extra centrosomes thatsegregate chromosomes in the presence of multipolarspindles (1). The number of spindle poles in mitosis isdetermined by centrosomes, discrete organelles that nucle-ate spindle microtubules. Centrosome copy number isunder strict cell cycle regulation. Centrosomes duplicatein S phase so that normal cells enter mitosis with 2centrosomes and equally segregate replicated chromo-somes using bipolar spindles (Figs. 1A and 2A; ref. 2).Cells with extra centrosomes can undergo anaphase withmultipolar spindles and segregate chromosomes impro-perly to more than 2 daughter cells (Figs. 1C and 2B). Wecall this lethal event for each daughter cell (3, 4) anaphasecatastrophe. Anaphase catastrophe selectively targets cancercells with extra centrosomes and spares normal cells thatenter mitosis with only 2 centrosomes and, therefore, are

incapable of segregating chromosomes to more than 2spindle poles.

Targeting chromosomally unstable cancer cellsRecent work revealed a mechanism that induces cell

death preferentially in cancer cells with chromosomalinstability (CIN; ref. 1). This mechanism can beexploited therapeutically. CIN is common in aneuploidtumor cells and is usually caused by the persistence ofinappropriate attachments of chromosomes to spindlemicrotubules (5–7). The prevalence of attachment errorsincreases sharply in cells with extra centrosomes, owingto the key role of centrosomes in determining the num-ber of spindle poles during mitosis (3, 8). Cancer cellsgain extra copies of centrosomes either from failure ofcytokinesis or by deregulation of the strict cell cyclecontrol of centrosome duplication. Because chromosomesegregation is vital for cell survival, cancer cells with extracentrosomes assemble bipolar spindles in mitosis byclustering supernumerary centrosomes together at spin-dle poles (3, 4, 8).

Many biochemical pathways promote centrosome clus-tering during mitosis. Initial evidence shows that thesepathways can be pharmacologically targeted to induceanaphase catastrophe (Fig. 2C). A genome-wide screenusing Drosophila-cultured cells identified 133 distinct genesrequired for centrosome clustering (4). The products ofthese genes participate in diverse cellular processes, includ-ing regulation of the actin cytoskeleton, spindle assembly,spindle assembly checkpoint (SAC) activity, and cell adhe-sion. Positive hits in that screen that represent potential

Authors' Affiliations: 1Department of Pharmacology and Toxicology,2Department of Biochemistry, 3Norris Cotton Cancer Center, and 4Depart-ment of Medicine, Dartmouth Medical School, Hanover, New Hampshire;and Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

Note: F. Galimberti and S. L. Thompson contributed equally to this work.

Corresponding Author: Ethan Dmitrovsky, Department of Pharmacologyand Toxicology, Dartmouth Medical School, Remsen 7650, Hanover,NH 03755. Phone: 603-650-1707; Fax: 603-650-1129; E-mail:ethan.dmitrovsky@dartmouth.edu

doi: 10.1158/1078-0432.CCR-10-1178

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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targets for inhibition include the mitotic kinesin HSET,myosin 10A, and the enzyme tankyrase, which modifiesproteins involved in spindle pole organization. HSET is notrequired for mitosis in normal somatic cells with 2 centro-somes (9). Loss of HSET function in cells with supernu-merary centrosomes can induce anaphase catastrophespecifically within cells having extra centrosomes (4). Thisfinding provides a proof of principle that targeted inhibi-tion of these enzymes causes anaphase catastrophe andjustifies the search for inhibitors of these enzymes or othertargets that might cause anaphase catastrophe. The powerof the genetic screens is offset by the fact that the strategywill only identify target genes whose products function at aspecific phase of the cell cycle. Other biochemical pathwaysmight participate in centrosome clustering. These pathwaysrepresent additional opportunities for inducing anaphasecatastrophe. As one example, lung cancers often overex-press cyclin E, which can deregulate cyclin-dependentkinase (Cdk) activity (10). Targeting Cdk2, one of thesederegulated kinases, triggers anaphase catastrophe (1).Cell viability relies on the equal separation of replicated

chromosomes during mitosis. Mitotic fidelity is enhancedby the SAC (11). The SAC prevents sister chromatid separa-tion and anaphase onset until all chromosomes formappropriate bipolar attachments to spindle microtubules.A single unaligned or unattached chromosome is sufficientto maintain SAC activity and prevent entry into anaphase(12, 13). Thus, a defined sequence of events is strictlyfollowed to ensure accurate chromosome segregation in

normal cells. Chromosomes form attachments to spindlemicrotubules and align at the equator of a bipolar spindle;that satisfies the SAC leading to activation of the ubiquitinligase anaphase promoting complex/cyclosome (APC/C).APC/C subsequently triggers degradation of securin andthe mitotic cyclin B to induce sister chromatid separationand exit from mitosis, respectively, so that daughter cellsenter G1 phase of the next cell cycle with the appropriatenumbers of chromosomes (14).

Anaphase catastrophe versus mitotic catastropheChemotherapeutic drugs such as paclitaxel disrupt

microtubule dynamics and chromosome attachment tospindle microtubules (15); this prolongs mitosis by pre-venting satisfaction of the SAC. The cellular response toprolonged mitotic arrest varies depending on the cell lineand even among cells within the same cell line; the out-come of this response depends on processes that regulatecyclin B levels (16, 17). Cyclin B quantities graduallydecrease and apoptotic signals gradually increase in mitoticcells. In some cells, mitosis can be sufficiently prolonged byantimitotic drugs, which promote apoptotic signals thatcan exceed a critical threshold and induce death in mitosis.In other cells, cyclin B levels drop below a critical thresholdduringmitotic arrest and cells exit mitosis and reenter G1 astetraploid cells without chromosome segregation. Thesetetraploid cells typically enter senescence or undergo apop-tosis (Fig. 1B), although some propagate and endocycle(16). Exit from mitosis without chromosome segregation

© 2011 American Association for Cancer ResearchR2011 AAmerican Association for CancCA i A i ti f CA i ti f C

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G2 M FATE

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Tetraploidy

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Figure 1. Fates of mitotic cells. Cells can undergo diverse fates according to their status at anaphase. A, proper segregation of chromosomes in mitosisleads to the generation of 2 genetically identical daughter cells. B, gradual degradation of cyclin B in the presence of prolonged spindle checkpoint activationcauses cells to exit mitosis without dividing chromosomes in anaphase, termed slippage. Cells that exit mitosis via slippage enter G1 as tetraploid cells. Thesecells may continue to cycle, senesce, or undergo apoptosis. C, anaphase catastrophe occurs when a cell with multiple centrosomes fails to coalescecentrosomes into 2 spindle poles and enters anaphasewith amultipolar spindle. Segregation of chromosomes tomore than 2 daughter cells causes cell death.

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following extended mitotic arrest has been termed adapta-tion because cells are said to "adapt" to prolonged check-point activity (18). Perhaps a more appropriate term forthis is mitotic slippage, because cells slip out of mitosis

without satisfying the SAC (17, 19). Notably, mitoticslippage or adaptation violates the temporal sequence ofevents needed for proper chromosome segregation becausecells enter G1 of the next cell cycle without satisfying theSAC or adequately activating APC/C. Cancer cells with CINare no more likely to continue cycling following mitoticslippage than are diploid cells (16), indicating that thisalone does not selectively kill tumor cells. Nonetheless, it isproposed that substantial DNA damage conferred by che-motherapeutic agents or mutation of DNA damageresponse genes can promote cell death during mitosis ormitotic slippage (collectively known as mitotic catastrophein ref. 20) of cancer cells. Cells that enter anaphase withmultipolar spindles abide by the appropriate temporalsequence of biochemical events for mitotic exit and onlyinitiate chromosome separation after all chromosomes areattached to the spindle. This event is mechanistically dis-tinct from mitotic slippage or adaptation, which is why wetermed it anaphase catastrophe.

Clinical-Translational Advances

An established paradigm for cancer therapy involvestargeting and killing dividing cells. Many chemotherapeu-tic agents target dividing cells during mitosis, which is asensitive window in the cell cycle during which chromo-somes align and separate to form genetically identicaldaughter cells. Taxanes and vinca alkaloids successfully killtumor cells during mitosis by targeting microtubules anddisrupting normal chromosome movement. However,these drugs are not specific to cancer cells and disruptmicrotubules in all cells, leading to side effects such asneutropenia and neurotoxicity (15). Nevertheless, thesedrug effects establish that mitotic disruption is engagedby chemotherapy treatments. On the basis of this finding,compounds are being developed that inhibit proteins thatonly function during mitosis and would not target non-dividing cells. Clinical trials are underway to explore theefficacy of inhibitingmolecularmotors required for bipolarspindle organization (21) and of inhibitors of the essentialAurora and Polo-like kinases (22, 23). Yet, these drugstarget actively dividing cells and do not necessarily exploitkey differences between malignant and benign cells, whichmight spare normal cells. For example, cells in most solidtumors are aneuploid with chromosome numbers thatdeviate from a multiple of the haploid genome. The roleof aneuploidy in tumorigenesis is under study throughexperiments conducted in clinically relevant animal mod-els (24, 25). To date, those efforts have not identifiedspecific treatment strategies that would selectively targetaneuploid cells and spare diploid cells. However, the recentinsights into the causes of CIN (3, 26), described above,revealed that the proapoptotic mechanism of anaphasecatastrophe can be pharmacologically targeted to selec-tively kill tumor cells.

We recently showed that targeted depletion of Cdk2, butnot Cdk1, induced anaphase catastrophe in lung cancercells; current work is elucidating Cdk2 targets that mediate

© 2011 American Association for Cancer Research

A B

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Survival

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Cdk2 inhibitor

HSET inhibitor

ILK inhibitor Multipolar

spindle

formation

Supernumerary

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Centrosome

overduplication

Plk4 inhibitor

merican Associ tiation for Cancer Resea

Centrosome

Death

Figure 2. Inhibition of Cdk2 and other pathways triggers anaphasecatastrophe in lung cancer cells. Mouse lung cancer cells overexpressingcyclin E were treated with control siRNA, A, or Cdk2 targeting siRNA, B, for24 hours. Cells were stained for microtubules in red and DNA in blue. Arepresentative bipolar anaphase, A, and a representative multipolaranaphase leading to anaphase catastrophe, B, are shown. Scale bar, 10mm. C, pharmacologic or genetic inhibition of numerous pathways affectsmitotic fidelity and can trigger anaphase catastrophe leading to cell death.Centrosome amplification leads to supernumerary centrosomes, whichcan be prevented with a Plk4 inhibitor. Centrosome clustering enablescancer cells to survive through mitosis in the presence of supernumerarycentrosomes. Inhibition of Cdk2, HSET, or ILK inhibits centrosomeclustering, resulting in multipolar spindle formation; this causes multipolaranaphases that trigger anaphase catastrophe.

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this effect (Fig. 2B; ref. 1). Cdk inhibitors exist, and somesuch as flavopiridol and UCN-01 exert some clinical anti-tumor activity (27). Another inhibitor (seliciclib, CYC202,R-roscovitine) can preferentially inhibit Cdk2 at low con-centrations, whereas at higher concentrations inhibition ofCdk1, Cdk7, or Cdk9 is observed (28). Anaphase cata-strophe is induced when cells with extra centrosomes areexposed to seliciclib at dosages that should only targetCdk2 (1). Similar concentrations had minimal mitoticeffects on immortalized pulmonary epithelial cells, imply-ing differential activity against cancer cells (1). Even tran-sient exposures (4 hours) to a Cdk2 inhibitor increased thenumber of cells undergoing anaphase catastrophe, suggest-ing that the drug acts by inhibiting cyclin-dependent kinaseactivity during mitosis and not during centrosome duplica-tion in S phase (1). These and other findings provide aproof of principle for anaphase catastrophe induction aftertreatment with specific drugs. Future work should elucidatewhether mechanisms seen in vitro can be observed in vivovia proof-of-principle clinical trials.Consistent with this concept was the finding that integ-

rin-linked kinase (ILK) activity is essential for centrosomeclustering in cancer cells (29). ILK regulates actin and celladhesion at focal adhesion sites as well as microtubule-associated components during mitosis, likely through reg-ulation of Aurora A/TACC3/TOG activity (30). Small mole-cule inhibitors of ILK can induce anaphase catastrophewithin breast cancer cells with extra centrosomes, but notwithin normal cells or cancer cells without extra centro-somes (31). Therapeutic strategies that inhibit key targetenzymes or pathways responsible for centrosome cluster-ing are being uncovered that will selectively kill cancer cellswith extra centrosomes, while sparing normal cells. Animportant future direction for study is to identify down-stream targets of Cdk2 and ILK that are essential forcentrosome clustering. That search would likely revealother candidate targets that induce anaphase catastrophe.Intriguingly, drugs that induce anaphase catastrophe

seem to cooperate with taxanes. Taxanes are routinelyused in the treatment of breast, bladder, ovarian, headand neck, and lung cancer (15). These agents specificallytarget microtubules and disrupt the normal timing ofmitosis by delaying the satisfaction of the SAC. Treatmentof cells with combinations of either the Cdk2 inhibitor

seliciclib and taxanes or the ILK inhibitor QLT-0267 andtaxanes showed significant increases in cancer cell death(1, 31). In the case of combining seliciclib and taxanes,this increase was linked to augmented anaphase cata-strophe (1). These combinations likely force cells toundergo catastrophic anaphase more efficiently than witheither treatment alone. Combining an agent that inducesanaphase catastrophe with a microtubule-targeting drugis an attractive regimen to consider in future clinical trialsfor appropriate cancers.

In this regard, pharmacogenomic analysis revealed thatlung cancer cells with k-ras mutations are especially sensi-tive to Cdk2 inhibition (1). K-ras mutation typically pre-dicts resistance to an epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI; ref. 32). This muta-tion is found in most pancreatic cancers, in about 30% oflung cancers, and in many other cancers (33, 34). Thisfinding suggests that a regimen that augments anaphasecatastrophe is appealing to consider for treating cancersthat harbor ras mutations.

In conclusion, recent findings reveal anaphase in mitoticcells with multipolar spindles is a lethal event that ispharmacologically conferred. Anaphase catastrophe wouldselectively kill cancer cells with extra centrosomes and likelyspare normal cells. This unique pathway, identified inmitosis, could discriminate between cancerous and normalcells. Thus, anaphase catastrophe is a novel anti-neoplasticmechanism to engage for cancer therapy and prevention.

Disclosure of Potential Conflicts of Interest

E. Dmitrovsky previously received a research grant from Cyclacel. Theother authors disclosed no potential conflicts of interest.

Grant Support

This work was supported by NIH and National Cancer Institute (NCI) grantsRO1-CA087546 (E. Dmitrovsky) and RO1-CA111422 (E. Dmitrovsky); RO1-GM51542 (D. A. Compton); T32-GM008704 (S. L. Thompson); and a SamuelWaxman Cancer Research Foundation Award (E. Dmitrovsky and D.A. Comp-ton). E. Dmitrovsky is an American Cancer Society Clinical Research Professorsupported by a generous gift from the F. M. Kirby Foundation.

The costs of publication of this article were defrayed in part by the paymentof page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received September 23, 2010; revised November 23, 2010; acceptedDecember 1, 2010; published OnlineFirst February 2, 2011.

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