Modulating centrosome positioning as a pathway to chemotherapy

Microtubules form the fibers of the mitotic spindle that are required for the separation of the chromosomes during mitosis. Due to the elevated proliferation observed in cancer cells, a series of small molecules targeting microtubules still form a widely used category of anticancer agents. Unfortunately, given the critical role of the microtubule cytoskeleton in multiple aspects of cellular physiology, these therapies often induce multiple side-effects including alopecia, neuropathy, and neutropenia. The modes of action and subcategories of MT targeting agents have already been well-reviewed (Čermák et al., 2020; Lafanechère, 2022).

Targeting centrosome separation: In an effort to more specifically target proliferating cells, multiple pharmaceutical companies have developed drugs targeting the normal process of centrosome separating in prophase. The main target of this attempted therapy is Kinesin-5. Although some of these drugs have been deemed safe in early-phase clinical trials, they have exhibited limited efficacy (Shahin and Aljamal, 2022; Tischer and Gergely, 2019). One potential reason for this is that Kinesin-12 can rescue spindle assembly following Kinesin-5 inhibition (Sturgill and Ohi, 2013; Sturgill et al., 2016; Solon et al., 2022).

Targeting centrosome clustering: Another centrosome positioning pathway targeted for cancer therapy is “Centrosome Clustering.” Cancer cells often carry supernumerary centrosomes (Chan, 2011; Marteil et al., 2018), which would normally lead to chromosome missegregation and cell death due to multipolar spindle formation. In some cases, cancer cells overcome this obstacle by hijacking a Kinesin-14-based mechanism that pulls the centrosomes together, causing them to cluster and leading to bipolar spindle formation that escapes terminal multipolar-spindle division (Kwon et al., 2008; Chavali et al., 2016; Vitre et al., 2020). A popular and reasonable hypothesis in the field is that preventing centrosome clustering by inhibiting Kinesin-14 could specifically kill mitotic cancer cells. Thus far, targeting Kinesin-14 s has been effective in preventing centrosome clustering in cultured cells and mouse models, but there is yet to be any clinical trial data (Xiao and Yang, 2016). It is important to note that there is some evidence that, despite its effectiveness in preclinical models, targeting mitosis may not be a clinically effective strategy for treating cancers. It is possible that the effectiveness of microtubule-targeting drugs is due to the critical role microtubules play in the interphase cells that form the bulk of the tumor mass (Komlodi-Pasztor et al., 2011).