Targeting cell-cycle machinery in cancer

Suski, Jan M.; Braun, Marcin; Strmiska, Vladislav; Siciński, Piotr

doi:10.1016/j.ccell.2021.03.010

Cited by 281 publications

(213 citation statements)

References 174 publications

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“…Cancer is characterized by aberrant cell cycle activities, which occur either as a result of mutations in upstream signaling pathways or by genetic lesions in genes encoding cell cycle proteins [56]. Thus, cell cycle regulators are attractive targets, leading to recent FDA approval of several CDK4/6 inhibitors for human cancers [57][58][59][60][61]. However, frequent inactivation of RB1 by loss of function mutation or MCPyV enables MCC proliferation independent of CDK4/6 activity, making CDK4/6 inhibitors less effective in MCC.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Das

Kannan

Nguyen

et al. 2021

Cancers

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Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Das

Kannan

Nguyen

et al. 2021

Cancers

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“…Uncontrolled cell proliferation and abnormal activity of cell cycle proteins are at the basis of carcinogenesis. As a result, various cell cycle regulators have been considered as potential targets in cancer therapy ( Otto and Sicinski, 2017 ; Suski et al, 2021 ). Normal activity of Cyclin E/CDK2 complex is essential for appropriate cell cycle progression and DNA replication.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…Therefore, targeting oncogenic activity of Cyclin E/CDK2 complex (e.g. through Cyclin E-targeted degradation or CDK2-selective inhibition) may represent an attractive therapeutic strategy for specific cancer subtypes, such as breast, uterine, and ovarian cancers ( Tadesse et al, 2020 ; Suski et al, 2021 ).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…Hyperactivation of Cyclin E/CDK2 complex directly interferes with DNA replication through several mechanisms, leading to DNA double strand breaks (DSBs) and genomic instability. In fact, specific targeting of oncogenic Cyclin E/CDK2 complex has been proposed as a promising therapy against cancer ( Tadesse et al, 2020 ; Suski et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Fagundes

Teixeira

2021

Front. Cell Dev. Biol.

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DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.

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“…The G2/M cell transition period is the most important detection point for cell cycle growth, differentiation, and proliferation ( Galbraith et al, 2019 ). Therefore, tumor cell cycle arrest is among the common mechanisms of anti-tumor proliferation ( Suski et al, 2021 ). From the perspective of cell cycle, this study further clarified the mechanism underlying sempervirine’s inhibition of the proliferation of glioma cells (U251 and U87).…”

Section: Discussionmentioning

confidence: 99%

Sempervirine Mediates Autophagy and Apoptosis via the Akt/mTOR Signaling Pathways in Glioma Cells

Zhong

Wang

et al. 2021

Front. Pharmacol.

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The potential antitumor effects of sempervirine (SPV), an alkaloid compound derived from the traditional Chinese medicine Gelsemium elegans Benth., on different malignant tumors were described in detail. The impact of SPV on glioma cells and the basic atomic components remain uncertain. This study aimed to investigate the activity of SPV in vitro and in vivo. The effect of SPV on the growth of human glioma cells was determined to explore three aspects, namely, cell cycle, cell apoptosis, and autophagy. In this study, glioma cells, U251 and U87 cells, and one animal model were used. Cells were treated with SPV (0, 1, 4, and 8 μM) for 48 h. The cell viability, cell cycle, apoptosis rate and autophagic flux were examined. Cell cycle, apoptotic, autophagy, and Akt/mTOR signal pathway-related proteins, such as CDK1, Cyclin B1, Beclin-1, p62, LC3, AKT, and mTOR were investigated by Western blot approach. As a result, cells induced by SPV led to G2/M phase arrest and apoptosis. SPV also promoted the effect of autophagic flux and accumulation of LC3B. SPV reduced the expression of p62 protein and induced the autophagic death of glioma cells. Furthermore, SPV downregulated the expressions of AKT and mTOR phosphorylated proteins in the mTOR signaling pathway, thereby affecting the onset of apoptosis and autophagy in U251 cells. In conclusion, SPV induced cellular G2/M phase arrest and blockade of the Akt/mTOR signaling pathway, thereby triggering apoptosis and cellular autophagy. The in vivo and in vitro studies confirmed that SPV inhibits the growth of glioma cancer.

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Targeting cell-cycle machinery in cancer

Cited by 281 publications

References 174 publications

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis

Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability

Sempervirine Mediates Autophagy and Apoptosis via the Akt/mTOR Signaling Pathways in Glioma Cells

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