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found that trisomies of chromosome 4 and 6 did not affect prognosis in patients with high hyperdiploid
acute lymphoblastic leukemia, while concurrent trisomies of chromosomes 10 and 17 were associated with
a better prognosis and trisomies of chromosome 5 was correlated with a worse prognosis. Later on, in this
manuscript, we describe two approaches to target chromosome instability clinically. The first is by targeting
some key proteins involved in the centrosome duplication cycle to decrease chromosome instability. The
second approach aligns more with the notion that the cell will tolerate a certain level of chromosome
instability and beyond that the cell will not be viable. Therefore, this approach aims to elevate chromosome
instability levels to induce cell cycle arrest or apoptosis.

INHIBITORS OF CHROMOSOME INSTABILITY IN CANCER TREATMENT
Given the numerous mechanisms attributed to chromosomal instability, several approaches have been
proposed to target chromosome instability in cancer. One approach is to target centrosome-associated proteins
that regulate microtubule dynamics and the SAC to prevent centrosome amplification, thus preventing
chromosome instability [87,189,190] . The Cdk4/Cdk6 inhibitor Palbociclib (PD-0332991) in combination with
+
-
the aromatase inhibitor letrozole has greatly improved the outcomes of ER , Her2 advanced breast cancer
patients [191,192] . Albeit that study did not measure centrosome amplification and chromosome instability,
it is tempting to propose this as an approach to suppress active generation of these processes in cancer
cells, since we have shown that silencing or genetic ablation of Cdk4 in p53-null fibroblasts, in mammary
epithelial cells expressing H-Ras G12V or H-Ras G12V and c-Myc, or in Her2 breast cancer cells suppress these
+
processes [25,104,174] . However, this approach neglects the fact that chromosome instability may occur by multiple
mechanisms and multiple dysregulated proteins. In fact, Palbociclib is ineffective in basal breast cancer cells
(the subtype with a higher degree of chromosome instability), and patients are harboring alterations in
the Rb/E2F pathway [193,194] . Nevertheless, several inhibitors targeting polo-like kinases (Plks) and Aurora
kinases (AURKs) have been tested in pre-clinical and clinical trials with mixed outcomes, and this has been
extensively discussed elsewhere . Notably, the inhibitor MLN8237 (Asertib) that targets AURKs exhibited
[189]
efficacy for several solid tumors and T-cell lymphoma, but not acute myeloid leukemia [195,196] . The opposite
was observed for the selective inhibitor of AURKB, AZD1152 (Barasertib) .
[189]

Another strategy to kill tumor cells is to elevate chromosome mis-segregation. It has been proposed that
there is an optimal level of chromosome instability for tumor maintenance and progression; beyond that
level chromosome instability becomes detrimental for cancer cells [12,184] . For example, elegant experiments
from the Sluder laboratory demonstrated that the acquisition of tetraploidy in most immortalized or cancer
cells they investigated resulted in cell cycle arrest within a few cell cycles . Also, the Cleveland group
[140]
demonstrated that while low-level aneuploidy triggered by the loss of one copy of Cenp-E was tumor
promoting in mice, aneuploidy can also be tumor-suppressive . A recent pan-cancer analysis of genetic
[197]
heterogeneity in cancer done by the Malley group showed that in general, cancers with intermediate levels
of chromosome instability (measured by copy number variation analysis) had worst prognosis than cancers
with low or high levels of instability . However, their relationship varied depending of the adjuvant treatment
[2]
given, suggesting that radiotherapy and adjuvant chemotherapy may be effective in treating cancers with
intermediate chromosome instability by pushing the limits of tolerable chromosome instability. The
Swanton’s group also provided clinical evidence to support this hypothesis with their retrospective study
conducted in a cohort of 246 primary breast cancer patients . The study showed that extreme chromosome
[12]
instability (measured with chromosome-specific markers and aCGH and correlated to the CIN70 score,
MammaPrint, and GGI) correlated with improved long-term survival in ER-negative breast cancer patients;
exhibiting a non-monotonic correlation . This observation was confirmed in a study involving a larger
[12]
cohort of ER patients . However, a linear correlation was observed in ER-positive breast cancer patients
-
[198]
and extreme chromosome instability ; the same relationship was found with glioblastomas . Thus, we have
[2]
[12]