Molecular Pathways: Targeting the Cyclin D–CDK4/6 Axis for Cancer Treatment

VanArsdale, Todd; Boshoff, Chris; Arndt, Kim; Abraham, Robert T.

doi:10.1158/1078-0432.ccr-14-0816

Cited by 324 publications

(262 citation statements)

References 58 publications

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“…Although single-agent activity has been revealed in various cancer types, their major values appear to be in combination therapy to enhance efficacy of other systemic therapies (31). Our data support the use of CDK inhibitors in combination therapy for hepatocellular carcinoma.…”

Section: Discussionsupporting

confidence: 63%

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu

Lin

Cheng

et al. 2016

Clinical Cancer Research

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Purpose: To clarify the effects of cyclin E1 suppression on antitumor efficacy of sorafenib in hepatocellular carcinoma cells and to explore the potential of combining sorafenib with cyclindependent kinase (CDK) inhibition in therapy.Experimental Design: The effects of cyclin E1 suppression on sorafenib-induced apoptosis were tested in both sorafenibsensitive (Huh-7 and HepG2, IC 50 5-6 mmol/L) and sorafenib-resistant (Huh-7R and HepG2R, IC 50 14-15 mmol/L) hepatocellular carcinoma cells. The activity of pertinent signaling pathways and the expression of cell cycle and apoptosisrelated proteins were measured using Western blotting. Efficacy of sorafenib combined with the pan-CDK inhibitor flavopiridol was tested both in vitro and in xenograft experiments. The pertinent downstream mediators of antitumor efficacy were tested in transient transfection and RNA interference experiments.Results: Cyclin E1 mRNA and protein expressions were suppressed after sorafenib treatment in sorafenib-sensitive but not in sorafenib-resistant hepatocellular carcinoma cells. Changes in cyclin E2 or D1 were not correlated with sorafenib sensitivity. The knockdown of cyclin E1 expression reversed the resistance of hepatocellular carcinoma cells to sorafenib in terms of cell growth and apoptosis induction, whereas the overexpression of cyclin E1 increased the resistance to sorafenib. The growth-inhibitory and apoptosis-inducing effects of sorafenib were enhanced by flavopiridol, and Mcl-1 suppression was determined to play a critical role in mediating this enhancing effect.Conclusions: The cyclin E1 suppression in hepatocellular carcinoma cells may serve as a pharmacodynamic biomarker for predicting sorafenib efficacy. The combination of sorafenib and CDK inhibitors may improve the efficacy of sorafenib in hepatocellular carcinoma.

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Section: Discussionsupporting

confidence: 63%

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Hsu

Lin

Cheng

et al. 2016

Clinical Cancer Research

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“…Thus, the CyclinD-CDK4/6-pRB pathway has been exploited as a therapeutic target (34,35). Additionally, the present cellular model for triple negative breast cancer subtype harbors a gain-of-function R280K mutation in the tumor suppressor TP53 gene that confers survival advantage via the upregulation of cell migration and invasion (36).…”

Section: Biomarkermentioning

confidence: 99%

Growth inhibitory efficacy of natural products in a model for triple negative molecular subtype of clinical breast cancer

Telang¹

2017

Biomedical Reports

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Abstract. Global gene expression profiling identifies predictive and prognostic biomarkers and rationalizes breast cancer subtype-targeted treatment. The Anthracyclin/Taxol and survival pathway specific small molecular inhibitors, constitute current treatment options. These options are associated with acquired tumor resistance and emergence of drug-resistant cancer stem cells. Dietary supplements and constitutive bioactive phytochemicals with relatively low systemic toxicity may provide testable alternatives for current therapy. Human breast epithelial cell lines 184-B5 (non-tumorigenic triple negative cell type) and MDA-MB-231 (breast carcinoma derived triple negative cell type) were used as the experimental models. Putative cancer chemo-preventive natural products and their constitutive bioactive agents represented the test agents. Anchorage independent growth, cell cycle progression and cell apoptosis quantified the treatment efficacy. Compared to the 184-B5 cells, the MDA-MB-231 cells exhibited anchorage-independent growth indicative of persistent cancer risk. Additionally, the MDA-MB-231 cells exhibited hyper-proliferation, accelerated cell cycle progression and inhibited apoptosis indicative of loss of homeostatic growth control. The test agents inhibited anchorage-independent growth via cytostatic and pro-apoptotic effects. The triple negative carcinoma-derived Doxorubicin-resistant phenotype exhibited cancer stem cell markers, including tumor spheroid formation and expression of CD44, NANOG and c-Myc. These data identify clinically relevant mechanistic leads for the efficacy of natural products in the aggressive therapy-resistant breast cancer subtype and suggests a testable approach for cancer stem cell-targeted therapy.

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“…В случае фосфорилирования CDK4 / 6 белок RB1 теряет свои супрессорные свойства, и клетка приобре-тает способность к делению. Такой же эффект отмеча-ется и при мутационной инактивации белка RB1, наблюдаемой во многих разновидностях новообразо-ваний [21,22].…”

Section: опухоли женской репродуктивной системы Tumors Of Female Reprunclassified

“…Мыши, у которых посред-ством генно-инженерных манипуляций нокаутирован ген CDK4, становятся менее чувствительными к воз-действию канцерогенов. Применение различных ин-гибиторов CDKs замедляет деление опухолевых клеток в условиях in vitro, а также приводит к регрессии ново-образований у экспериментальных животных [21,22].…”

Section: опухоли женской репродуктивной системы Tumors Of Female Reprunclassified

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Evolution of systemic treatment for hormone-sensitive breast cancer: from sequential use of single agents to the upfront administration of drug combinations

Имянитов¹

2016

Tumors of female reproductive system

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Molecular Pathways: Targeting the Cyclin D–CDK4/6 Axis for Cancer Treatment

Cited by 324 publications

References 58 publications

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

Growth inhibitory efficacy of natural products in a model for triple negative molecular subtype of clinical breast cancer

Evolution of systemic treatment for hormone-sensitive breast cancer: from sequential use of single agents to the upfront administration of drug combinations

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