Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Lukow, Devon A.; Sausville, Erin L.; Suri, Pavit; Chunduri, Narendra Kumar; Wieland, Angela; Leu, Justin; Smith, John K.; Girish, Vishruth; Kumar, Ankith A.; Kendall, Jude; Wang, Zihua; Storchová, Zuzana; Sheltzer, Jason M.

doi:10.1016/j.devcel.2021.07.009

Cited by 151 publications

(132 citation statements)

References 67 publications

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“…Non small lung cancer (NSCLC) cells frequently exhibit high levels of whole chromosome instability (nCIN), a feature that has been experimentally linked to acquired drug resistance [1, 3–6, 22]. To understand the molecular changes that correspond with segregation errors and nCIN in NSCLC cells we first identified a panel of NSCLC cell lines that exhibit mitotic defects and chromosome copy number heterogeneity consistent with nCIN (A549, H1299, and PC9; [21]).…”

Section: Resultsmentioning

confidence: 99%

Suppression of chromosome instability limits acquired drug resistance

Manning¹,

Hermance²,

Crowley³

et al. 2020

Preprint

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Chromosome instability, or CIN, defined as a high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. CIN has been shown to promote intra-tumor heterogeneity and correspond with tumor aggressiveness, drug resistance and tumor relapse. However, whether CIN promotes the acquisition of genomic changes responsible for drug resistance remain unclear. Here we assess the role of CIN in the acquisition of drug resistance in non small cell lung cancer. We show that impairment of centromeric cohesion underlies the generation of whole chromosome segregation errors and CIN in non small cell lung cancer cells. Further, we demonstrate that centromere-specific enhancement of chromosome cohesion strongly suppresses CIN and reduces intra-tumor heterogeneity. We demonstrate that suppression of CIN has no impact on NSCLC cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of CIN alters the timing and molecular mechanism that drive acquired drug resistance. These findings suggest mechanisms to suppress CIN may serve as effective co-therapies to limit tumor evolution and sustain drug response.

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Section: Resultsmentioning

confidence: 99%

Suppression of chromosome instability limits acquired drug resistance

Manning¹,

Hermance²,

Crowley³

et al. 2020

Preprint

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show abstract

“…In this review, we have discussed how chromosome segregation errors induce DNA damage and how this exacerbates genome instability in the resulting aneuploid cells, a condition that has recently been shown to confer proliferative advantages under specific conditions ( Ippolito et al, 2021 ; Lukow et al, 2021 ; Salgueiro et al, 2020 ) ( Figure 1 ). It has to be noted that the vast majority of studies conducted so far have employed an heterogenous population of aneuploid cells, comprising both chromosome gains and losses as well as cycling and arrested cells.…”

Section: Discussionmentioning

confidence: 99%

“…This seems to be particularly relevant to cancer cells, which are found to be very often aneuploid (Vasudevan et al, 2021). In fact, recent work has shown that abnormal chromosome number in the context of cancer can promote resistance to chemotherapy (Salgueiro et al, 2020;Ippolito et al, 2021;Lukow et al, 2021), in line with the observation that highly aneuploid tumors correlate with poorer patient outcomes (Davoli et al, 2017;Vasudevan et al, 2020). In details, chromosome missegregation events cause increased karyotypic heterogeneity that can be utilized by cancer cells to find the correct karyotypic landscape and thus survive under selective pressures such as chemotherapy.…”

Section: Consequences Of Genomic Instability On Aneuploid Cell Fitnessmentioning

confidence: 99%

The Dynamic Instability of the Aneuploid Genome

Garribba

Santaguida

2022

Front. Cell Dev. Biol.

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Proper partitioning of replicated sister chromatids at each mitosis is crucial for maintaining cell homeostasis. Errors in this process lead to aneuploidy, a condition in which daughter cells harbor genome imbalances. Importantly, aneuploid cells often experience DNA damage, which in turn could drive genome instability. This might be the product of DNA damage accumulation in micronuclei and/or a consequence of aneuploidy-induced replication stress in S-phase. Although high levels of genome instability are associated with cell cycle arrest, they can also confer a proliferative advantage in some circumstances and fuel tumor growth. Here, we review the main consequences of chromosome segregation errors on genome stability, with a special focus on the bidirectional relationship between aneuploidy and DNA damage. Also, we discuss recent findings showing how increased genome instability can provide a proliferation improvement under specific conditions, including chemotherapeutic treatments.

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“…The phenotypic plasticity in combination with tumour heterogeneity enables CIN tumours to rapidly adapt to diverse stress conditions. It has been shown that CIN permits and accelerates the acquisition of resistance against anti-cancer therapies by acquiring recurrent copy number changes [24,25]. This acquired drug resistance could potentially exacerbate the intrinsic drug resistance [26] of many CIN cells, which highlights the need to better understand genomic changes of CIN tumours in the context of anti-cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Distinct and Common Features of Numerical and Structural Chromosomal Instability across Different Cancer Types

Zhang

Kschischo

2022

Cancers

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A large proportion of tumours is characterised by numerical or structural chromosomal instability (CIN), defined as an increased rate of gaining or losing whole chromosomes (W-CIN) or of accumulating structural aberrations (S-CIN). Both W-CIN and S-CIN are associated with tumourigenesis, cancer progression, treatment resistance and clinical outcome. Although W-CIN and S-CIN can co-occur, they are initiated by different molecular events. By analysing tumour genomic data from 33 cancer types, we show that the majority of tumours with high levels of W-CIN underwent whole genome doubling, whereas S-CIN levels are strongly associated with homologous recombination deficiency. Both CIN phenotypes are prognostic in several cancer types. Most drugs are less efficient in high-CIN cell lines, but we also report compounds and drugs which should be investigated as targets for W-CIN or S-CIN. By analysing associations between CIN and bio-molecular entities with pathway and gene expression levels, we complement gene signatures of CIN and report that the drug resistance gene CKS1B is strongly associated with S-CIN. Finally, we propose a potential copy number-dependent mechanism to activate the PI3K pathway in high-S-CIN tumours.

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Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Cited by 151 publications

References 67 publications

Suppression of chromosome instability limits acquired drug resistance

Suppression of chromosome instability limits acquired drug resistance

The Dynamic Instability of the Aneuploid Genome

Distinct and Common Features of Numerical and Structural Chromosomal Instability across Different Cancer Types

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