Tuning Chromosomal Instability to Optimize Tumor Fitness

Burkard, Mark E.; Weaver, Beth A.

doi:10.1158/2159-8290.cd-16-1415

Cited by 12 publications

(9 citation statements)

References 10 publications

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“…In a preclinical setting, we recently described delay of mitotic exit as a mechanism of TNBC resistance to the clinical TTK inhibitor, CFI-402257 using CRISPR/Cas9 functional genomic screens [73] ( Figure 2(d)). Our findings independently validated those of Sansregret et al who identified the same mechanism of resistance using siRNA screens with the tool compound reversine, another TTK inhibitor [74,75]. Both studies identified that compromising the anaphase-promoting complex/cyclosome (APC/C) function through genetic inactivation or knockdown of individual APC/C components led to elongation of mitosis with fewer chromosome segregation errors and consequentially, less cell death in cancer cells treated with TTK inhibitors.…”

Section: Ttk Inhibitorssupporting

confidence: 85%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

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Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

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Section: Ttk Inhibitorssupporting

confidence: 85%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

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“…These markers could potentially indicate patients with intrinsic resistance to CFI-402257. Characterization of these APC/C low cancers may reveal alternative vulnerabilities that could be exploited (29). Assessment of the APC/C metagene, other biomarkers of APC/C functional capacity, or somatic alterations in components of the APC/C pathway in ongoing clinical trials will determine the clinical significance of our findings.…”

Section: Discussionmentioning

confidence: 93%

“…The identification of the APC/C as a central complex mediating sensitivity to CFI-402257 is directly relevant to the rationale for TTK inhibition in TNBC, whereby the characteristic genomic instability of these tumors was identified as a therapeutic vulnerability that can be exploited by TTK-targeting agents (11). Inhibition of TTK in these tumors will cause synthetic lethality by abrogating the SAC and consequently increase aneuploidy to intolerable levels that lead to cancer cell death (29). Our study carried out in TNBC cell lines has revealed multiple components of the APC/C, which promotes mitotic progression into anaphase, as well as additional genes involved in initiating mitotic exit.…”

Section: Discussionmentioning

confidence: 99%

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer

Thu

Silvester

Elliott

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.

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“…Therefore, the propagation of CIN in cancer can arise through inactivation or bypass of the p53 pathway and the acquisition of mechanisms that allow tolerance of replication stress and aneuploidy-associated stressors, such as activation of the proteasome and autophagy and CIN adaptation [198,229,231]. While low and moderate levels of CIN may allow the evolution of advantageous karyotypes and the emergence of genomic alterations that provide resistance to therapy, tumors may not tolerate high CIN levels [232][233][234][235][236][237][238].…”

Section: Emerging Concepts: Chromosomal Instability/aneuploidy Toleramentioning

confidence: 99%

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Wilhelm

Said

Naim

2020

Genes

106

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Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.

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Tuning Chromosomal Instability to Optimize Tumor Fitness

Cited by 12 publications

References 10 publications

Targeting the cell cycle in breast cancer: towards the next phase

Targeting the cell cycle in breast cancer: towards the next phase

Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

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