PARP6 inhibition as a strategy to exploit centrosome clustering in cancer cells?

Centrosomes function as the main microtubule-organizing centers (MTOCs) and play an essential role during cellular mitosis. As such, centrosome number is tightly controlled, with centrosomes duplicated only once per cell cycle [1]. Unsurprisingly, centrosome abnormality, in particular centrosome amplification, has been frequently observed in human malignancies and is linked with aneuploidy and tumorigenesis. Recently the causative role of centrosome amplification in cancer has been demonstrated in a mouse model [2]. The resulting extra centrosomes from amplification pose a challenge for the proper execution of mitosis since multipolar mitosis is often detrimental to dividing cells and can lead to cell death [3]. Cancer cells, however, have developed tactics to avoid deleterious spindle multipolarity during mitosis through mechanisms such as centrosome clustering, a process that involves assembling multiple centrosomes into pseudo-bipolar spindles and thereby promotes tumor survival [4]. In recent years, a therapeutic strategy to pharmacologically impair centrosome clustering has emerged and demonstrated early promise in the preclinical setting: the goal is to exploit the vulnerability of cancer cells in handling spindle multipolarity by inducing centrosome de-clustering and achieve selective killing of cancer cells while sparing normal tissues