TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination

Chandler, Benjamin C.; Moubadder, Leah; Ritter, Cassandra L.; Liu, Meilan; Cameron, Meleah; Wilder-Romans, Kari; Zhang, Amanda; Pesch, Andrea M.; Michmerhuizen, Anna R.; Hirsh, Nicole; Androsiglio, Marlie P.; Ward, Tanner; Olsen, Eric; Niknafs, Yashar S.; Merajver, Sofía D.; Thomas, Dafydd G.; Brown, Powel H.; Lawrence, Theodore S.; Nyati, Shyam; Pierce, Lori J.; Chinnaiyan, Arul M.; Speers, Corey

doi:10.1172/jci130435

Cited by 55 publications

(46 citation statements)

References 62 publications

(66 reference statements)

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“…Ongoing clinical trials are evaluating CDK4/6 inhibitors in combination with radiotherapy in patients with bone metastases and oligometastatic breast cancer [29,30]. Similar to our results, an inhibitor of the spindle assembly checkpoint control protein TTK has been shown in preclinical studies to confer radiosensitization effects and substantially improved tumor control in TNBC [31]. Our findings support development of further preclinical studies of this combination and its molecular mechanisms, as well as early clinical trials to evaluate safety/toxicity in patients with metastatic breast cancer.…”

Section: Discussionsupporting

confidence: 85%

Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

et al. 2021

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Development of novel multimodality radiotherapy treatments in metastatic breast cancer, especially in the most aggressive triple negative (TNBC) subtype, is of significant clinical interest. Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.

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Section: Discussionsupporting

confidence: 85%

Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

et al. 2021

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“…Finally, the evaluation of TTK, the spindle assembly checkpoint kinase, also confirmed its role in dysregulation of HR and genome stability in EAC. This is also consistent with a recent report demonstrating the role of TTK in HR in breast cancer 32 . TTK has been identified as one of the promising candidates for vaccination in esophageal cancer patients with advanced stage disease 33,34 .…”

Section: Discussionsupporting

confidence: 94%

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Kumar

Buon

Talluri

et al. 2020

Preprint

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Identification of genes driving genomic evolution can provide novel targets for cancer treatment and prevention. Here we show identification of a genomic instability gene signature, using an integrated genomics approach. Elevated expression of this signature correlated with poor survival in esophageal adenocarcinoma (EAC) as well as three other human cancers. Knockout and overexpression screens confirmed the relevance of this signature to genomic instability. Indepth evaluation of TTK (a kinase), TPX2 (spindle assembly factor) and RAD54B (recombination protein) further confirmed their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrated that DNA damage and homologous recombination were common mechanisms of genomic instability induced by these genes. Consistently, a TTK inhibitor impaired EAC cell growth in vivo, and increased chemotherapy-induced cytotoxicity while inhibiting genomic instability in surviving cells. Thus inhibitors of TTK and other genes identified in this study have potential to inhibit/delay genomic evolution and tumor growth. Such inhibitors also have potential to increase chemotherapy-induced cytotoxicity while reducing its harmful genomic impact in EAC and possibly other cancers.

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“…Mitotic phosphorylation liberates TTK/Mps1 coacervates from the kinetochore and promotes its cytoplasmic distribution. Since amplification of TTK/Mps1 promotes breast cancer progression, and inhibition of TTK/Mps1 kinase activity leads to improved outcomes in clinical oncology (90), it would be of interest to determine whether TTK/Mps1 forms coacervates with its chemical inhibitor at the kinetochore and whether coacervates at the kinetochore are involved in the underlying mechanism for interrogation of breast cancer progression (91,92). Pelkmans and colleagues show that another mitotic dual kinase, DYRK3, regulates membraneless organelles by preventing un-mixing of the cytoplasm into aberrant organelles during mitosis (93), indicating that, during cell division, the kinase activities of Mps1 and DYRK3 control the LLPS.…”

Section: Aberrant Llps and Chromosome Instabilitymentioning

confidence: 99%

Phase separation drives decision making in cell division

Liu

Wang

et al. 2020

Journal of Biological Chemistry

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Liquid-liquid phase separation (LLPS) of biomolecules drives the formation of subcellular compartments with distinct physicochemical properties. These compartments, free of lipid bilayers and therefore called membraneless organelles, include nucleoli, centrosomes, heterochromatin, and centromeres. These have emerged as a new paradigm to account for subcellular organization and cell fate decisions. Here we summarize recent studies linking LLPS to mitotic spindle, heterochromatin, and centromere assembly and their plasticity controls in the context of the cell division cycle, highlighting a functional role for phase behavior and material properties of proteins assembled onto heterochromatin, centromeres, and central spindles via LLPS. The techniques and tools for visualizing and harnessing membraneless organelle dynamics and plasticity in mitosis are also discussed, as is the potential for these discoveries to promote new research directions for investigating chromosome dynamics, plasticity, and inter-chromosome interactions in the decision-making process during mitosis.

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TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination

Cited by 55 publications

References 62 publications

Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

Phase separation drives decision making in cell division

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