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Page 12 of 20 Jusino et al. J Cancer Metastasis Treat 2018;4:43 I http://dx.doi.org/10.20517/2394-4722.2018.24

Defects in Chromosome instability
cytokinesis and tetraploidy Cancer progression and
chemoresistance through
intra-tumor heterogeneity
M1
M2
M1 M5
M3
Chromosome M4
instability inhibitors
-AURKs M2
M4
-Mps1 M5
-PLKs

Cancer initiation

Centrosome amplification Pseudobipolar spindles Chromosome instability and aneuploidy

Figure 2. Centrosome amplification leads to tumor initiation and cancer progression through intra-tumor heterogeneity. Two models
are described above. First, centrosome amplification leads to pseudobipolar spindles that culminate in chromosome instability and
aneuploidy. Second, centrosome amplification leads to defects in cytokinesis that culminates in chromosome instability and tetraploidy.
Both mechanisms converge to initiate cancer. Cancer progression and chemoresistance occurs and is maintained as a consequence of
intra-tumor heterogeneity. Chromosome instability inhibitors (e.g., AURKs, Mps1, and PLKs) are therapeutic targets that may prevent this
chain of events by targeting early steps of this process

to be careful with proposing increasing chromosome instability as a strategy against cancer, since it is tumor
suppressive in some cancers, and tumor promoting in others.

Mitotic kinases contribute to chemotherapy resistance, as illustrated by Janssen et al. , who demonstrated
[199]
that the reduction of essential levels of Mps1 and BubR1 sensitized several tumor cells to clinically relevant
doses of paclitaxel (an anti-mitotic drug commonly used in cancer treatment). On the other hand, inhibition
of these kinases did not induce cell death in normal cells. Currently, a Mps1 inhibitor is being tested in clinical
trial Phase 1 (BAY1161909) in triple negative breast cancer patients [200] . In this clinical trial, the Mps1 inhibitor
is administered along with paclitaxel (a microtubule-interfering agent) to induce tumor death by increased
chromosome mis-segregation [200] . A similar approach can be tested with the combination of paclitaxel and
BubR1, Hec1, Nek2, or Sgol1 inhibitors because all of these proteins play an important role in proper SAC
functioning and our studies have demonstrated their role in centrosome amplification and chromosome
instability downstream of the E2F activators [35,162,201] . Additionally, a study by Lee et al. ranked 62 different
[201]
anticancer drugs for their capacity to induce chromosome instability. The drugs evaluated in this study have
several mechanisms of action (e.g., antimicrotubule activity, DNA replication and damage response, mitotic
checkpoint inhibition, etc.) and can be evaluated in combination with inhibitors of centrosome-associated
proteins to see if the effect of increase chromosome instability is potentiated. Thus, these findings present
us with multiple possibilities that together with advances in precise medicine and technologies such as SCS
can be explored in cancer patients with specific tumor genotype/phenotype (intra-tumor heterogeneity) to
develop better treatment.

CONCLUSION
Failure to properly regulate the cell cycle and the centrosome cycle leads to centrosome aberrations. One
of such centrosome aberrations is centrosome amplification, which occurs in various cancer types. In our
model depicted in Figure 2, we summarize two known mechanisms that denote the role of centrosome