Targeting Mitosis in Cancer: Emerging Strategies

Abstract

The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle-targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013). DNMT3B may regulate epigenetic events to facilitate CRPC development (Hoffmann et al ., 2007).…”

“…AURKA is emerging as an important regulator of mitosis and a critical player in tumorigenesis. As such, AURKA is a hotly pursued in cancer therapy (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015). Additionally, OIP5 is also known as Mis18β which has recently been shown to play an important role in chromatid separation during mitosis (Nardi et al ., 2016; Stellfox et al ., 2016), adding another appealing feature for its inclusion in SigMuc1NW.…”

The Mitotic Protein Kinase Haspin and Its Inhibitors

“…Because of its role in controlling the activity of Aurora B and in maintaining the cohesion of centromeres and spindle poles, Haspin has become a relevant target for cancer therapy and is considered as an emerging anti-mitotic drug target [53,54].…”

Drosophila Aurora A regulates mitotic timing in cancer stem cells: Possible therapeutic implications

“…However, this strategy seems to be efficient because the severe gain and loss of chromosomes induced by SAC inhibition is not compatible with survival of the daughter cells. 4 We recently challenged this strategy in vivo by suppression of the SAC in fly tumor neural stem cells. Interestingly, the use of Drosophila melanogaster neural stem cells (or neuroblasts [NBs]) has recently been proven to be a traceable system in cancer stem cell biology.…”

“…These inhibitors include microtubule interfering agents and inhibitors against kinases required for spindle assembly and the SAC. 4 We believe that the contribution of Aurora A, and probably other kinases (such as one of its downstream effectors polo-like kinase 1, best known as PLK1), to mitotic timing deserves to be analyzed in human cells because the duration of mitosis seems to have a relevant impact on the response of tumor cells to chemotherapy. 5 Moreover, some tumor tissues display high levels of mitotic proteins that are normally degraded during mitotic exit, which is thought to be the consequence of the large number of cells undergoing mitosis.…”