Targeted Anti-Mitotic Therapies: Can We Improve On Tubulin Agents?

Jeffrey R. Jackson*; Denis R. Patrick*; Mohammed M. Dar*; Pearl S. Huang‡

In This Article

Abstract and Introduction


The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.


Inducing aberrant mitosis in tumour cells leads to mitotic arrest, the consequence of which can be, but is not always, cell death. Given the proven success of therapies that change microtubule dynamics such as the vinca alkaloids and taxanes in the clinical treatment of cancer ( Table 1 ), it is reasonable to consider non-structural components of mitosis as potential drug targets for therapy. The recent explication of mitosis into discrete morphological stages mediated by defined biochemical effectors has defined additional functions for the mitotic kinesins, Aurora kinases and polo-like kinases (PLKs), all of which are druggable target classes[1] (Fig. 1), Table 2 ). The dynamic assembly of the mitotic spindle is well characterized and has been reviewed elsewhere.[2] Although the rationale for targeting Aurora A, Aurora B[3] and PLK1 (Ref. 4) for cancer treatment are relatively well described, the mitotic kinesin, kinesin spindle protein (KSP; also known as EG5),[5] which is required for progression from prophase to prometaphase, and centromeric protein E (CENPE), which functions during transition from prometaphase to metaphase[6,7] and is a component of the mitotic checkpoint,[8] have only recently emerged as cancer treatment targets.

Figure 1.

The phases of mitosis. The progression of mitosis through the canonical morphological stages is shown. Specific druggable protein targets that function during mitosis are highlighted. Kinesin spindle protein (KSP) is required to establish mitotic spindle bipolarity through driving centrosome separation. Centromeric protein E (CENPE) is required for accurate chromosome congression at metaphase during mitosis. Aurora A is crucial for centrosome maturation and separation during early prophase. Aurora B is a member of the chromosomal passenger complex (CPC) and is involved in histone H3 phosphorylation, chromosomal condensation, chromosomal alignment on the metaphase plate, bi-polar centromere-microtubule attachments, spindle checkpoint and cytokinesis. During mitosis, Polo-like kinase 1 (PLK1) is involved in centrosome maturation and formation of the mitotic spindle. PLK1 is also required for exit from mitosis and the separation of sister chromatids during anaphase. PLK1 might also have a role in cytokinesis through the phosphorylation of the kinesin-like motor protein MKLP1.

That these targets are only expressed in dividing cells is attractive, as non-dividing differentiated cells should not be affected by target inhibition, therefore potentially enabling an improved therapeutic index relative to the existing anti-mitotic therapies that target tubulin. Nevertheless, some of the anti-tumour effects of the tubulin drugs might be attributed to interphase interactions with the tubulin cytoskeleton. The newer targets might not afford the opportunity to alter both the mitotic spindle and the cytoskeleton, although the potential for undiscovered roles outside mitosis remains. In further support of new mitotic targets, the explication of these molecular targets and pathways during mitosis enables target inhibition to be associated with tumour growth inhibition, and suggests the possibility of using pharmacodynamic markers to determine biologically effective dosing during drug development. The ability to dose to an effective level rather than to a maximally tolerated dose might also enable improved therapeutic indicies with these targeted anti-mitotic agents.

Although there are many positive aspects to targeting the mitotic kinases and kinesins, the molecular pathways through which tumour cells undergo cell death in response to mitotic arrest are not well defined. Apoptosis characterized by the activation of caspase 3 (an important downstream effector) has been observed in studies with many anti-mitotic agents.[9,10,11] However, an alternative mechanism of cell death termed mitotic catastrophe has also been described. Mitotic catastrophe does not have a strict definition, but shares many of the morphological and biochemical aspects of apoptosis.[12] It has been described as cell death that occurs from metaphase of mitosis in response to agents that cause DNA or mitotic-spindle damage. In this form it can be independent of caspase 3 and involve the activation of caspase 2. In addition, the role of the mitotic checkpoint (Fig. 2) as an effector of cell death in response to mitotic inhibitors is controversial. An intact mitotic checkpoint has been suggested as a requirement for response to a KSP inhibitor;[9] however, an alternative theory of the role of checkpoint signalling during mitosis suggests that the loss of checkpoints might permit cell death in response to mitotic damage or even be lethal alone.[13,14,15] Aurora B inhibitors seem to promote the latter mechanism.[16] It has become increasingly clear that the inhibition of different target proteins that function during mitosis can kill cells by distinct mechanisms and, furthermore, these mechanisms can be influenced by various genetic alterations that are often found in cancer. Nevertheless, it is difficult at present to use molecular means of preselecting which tumours are likely to respond to a particular targeted inhibitor of mitosis because our understanding of these downstream mechanisms is incomplete.

Figure 2.

The mitotic checkpoint. Crucial regulators of the mitotic checkpoint at the kinetochore are shown. On each kinetochore, when microtubules are captured and tension in these is detected, the checkpoint is satisfied and MAD2 is released, providing the biochemical signal to proceed to anaphase. Further detail on checkpoint regulation has been previously reviewed.[80] CDC, cell division cycle; CENPE, centromere protein E; MAD, mitotic arrest deficient.

In this Review we address what is known about the function of the mitotic kinesins and the mitotic kinases, and whether this knowledge can be used to identify reliable biomarkers that will predict the likelihood of tumour sensitivity or resistance to inhibitors of mitosis.


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