Small molecule inhibitors of mitotic progression


Year:

Session type:

Andrea Musacchio

IFOM-IEO Campus, Italy

Abstract

Both normal and cancer cells acknowledge that mitosis is a crucial phase of the cell cycle. In both normal and cancer cells, two feedback control mechanisms operate at the kinetochore-microtubule interface to preserve ploidy through mitosis:

1) An error correction mechanism, which protects from incorrect kinetochore-microtubule attachments, allowing the selective stabilisation of correct attachments and the destabilisation of incorrect attachments, thus promoting bi-orientation.

2) The spindle assembly checkpoint (SAC), which synchronises the metaphase-anaphase transition with the completion of kinetochore-microtubule attachment for all sister chromatid pairs in the cell.

While there are reasons to believe that both control mechanisms are usually preserved in cancer cells, it has been proposed that both feedback mechanisms may become less efficient in cancer cells. Chromosome instability, a frequent feature of cancer cells, is probably a consequence of the weakening of the feedback mechanisms operating in mitosis. Such weakening may allow a balance between change and conservation, whereby the rate of chromosome gain or loss during mitosis increases relative to normal cells, but only within limits that can be tolerated by cell physiology.

We have characterised several small-molecule inhibitors to rationalise 1) the role of two prominent mitotic kinases, Aurora B and Mps1, in the processes of SAC control and error correction, as well as 2) the mysterious relationship between these two kinases. Our data are consistent with a model in which Aurora B is at the apex of a pathway that promotes error correction as well as SAC activation. Aurora B controls the activation of Mps1 and its localisation, but Mps1 is not the only target of Aurora B in bi-orientation and in the SAC.

I will discuss why the proteins of the SAC may be good targets for cancer therapy and the possible drawbacks of this approach.