Targeting centrosome amplification, an Achilles' heel of cancer

Abstract

Due to cell-cycle dysregulation, many cancer cells contain more than the normal compliment of centrosomes, a state referred to as centrosome amplification (CA). CA can drive oncogenic phenotypes and indeed can cause cancer in flies and mammals. However, cells have to actively manage CA, often by centrosome clustering, in order to divide. Thus, CA is also an Achilles' Heel of cancer cells. In recent years, there have been many important studies identifying proteins required for the management of CA and it has been demonstrated that disruption of some of these proteins can cause cancer-specific inhibition of cell growth. For certain targets therapeutically relevant interventions are being investigated, for example, small molecule inhibitors, although none are yet in clinical trials. As the field is now poised to move towards clinically relevant interventions, it is opportune to summarise the key work in targeting CA thus far, with particular emphasis on recent developments where small molecule or other strategies have been proposed. We also highlight the relatively unexplored paradigm of reversing CA, and thus its oncogenic effects, for therapeutic gain.

Loss of CPAP expression promotes sustained EGFR signaling and Epithelial-Mesenchymal Transition in oral cancer cells

“…Overall, while higher centrosome amplification and aberrant centriole features are frequently reported phenotypes in cancer 62,[66][67][68] and elevated CPAP expression in OSCC is possibly the consequence of tumor progression-associated inflammation, our novel observations suggest that CPAP also exerts tumor preventive function in OSCC through promoting the homeostasis of EGFR and suppressing EMT.…”

“…Centrosome amplification and higher expression of centrosomal proteins are key features of many cancers 62,[66][67][68] . However, whether these feature are the cause of OSCC and other cancers, or a consequence of tumor progression associated events is largely unknown.…”

Fate of the M-phase-assembled centrioles during the cell cycle in theTP53;PCNT;CEP215-deleted cells

“…Supernumerary centrioles are frequently observed in diverse cancer cells (Chan, 2011;Marteil et al, 2018). Several ways to generate centriole amplification have been suggested, including centriole over duplication, de novo centrosome formation, fragmentation of overly elongated centrioles and cytokinesis failure (Sabat-Pospiech et al, 2019). Most of all, overexpression of PLK4 generates multiple daughter centriole during S phase (Habedanck et al, 2005;Kleylein-Sohn et al, 2007).…”

A novel compound that disrupts mitotic spindle poles in human cells

“…As mentioned above, low concentrations of Vinblastine cause disengagement of mother-daughter centrioles. In addition, cancer cells with high aneuploidy and amplified centrosomes typically rely on centrosome clustering mechanisms to form bipolar spindles(Leber et al 2010;Ogden et al 2012;Sabat- Pospiech et al 2019). C75 may promote de-clustering and loss of centrosome integrity as visualized by gamma-tubulin and centrin-2 staining, making it an attractive compound to explore for the treatment of cancers with high centrosome numbers(Sabat-Pospiech et al 2019).…”

“…In addition, cancer cells with high aneuploidy and amplified centrosomes typically rely on centrosome clustering mechanisms to form bipolar spindles(Leber et al 2010;Ogden et al 2012;Sabat- Pospiech et al 2019). C75 may promote de-clustering and loss of centrosome integrity as visualized by gamma-tubulin and centrin-2 staining, making it an attractive compound to explore for the treatment of cancers with high centrosome numbers(Sabat-Pospiech et al 2019). Indeed, different cancer cell lines have different proportions of cells with multipolar spindles after C75 treatment, presumably due to different genetic changes in their background including those that could impact centrosome integrity, clustering and/or microtubule dynamics(Fig.…”