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

Thu, Kelsie L.; Soria‐Bretones, Isabel; Mak, T. W.; Cescon, DW

doi:10.1080/15384101.2018.1502567

Cited by 133 publications

(96 citation statements)

References 102 publications

(134 reference statements)

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“…Commonly dysregulated phosphosites across the five cancer types were used for pathway annotation and led to the identification of the cell cycle pathway to be differentially regulated. Cell cycle is one of the most commonly reported activated pathways in cancer since decades [24][25][26][27][28][29]. A few kinases such as the cyclin dependent kinases (CDKs), checkpoint proteins, and other regulatory transcription factors synchronize and maintain the progress of cells through their division phase.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Global Proteomic and Phosphoproteomic Data Sets Revealed Activation of NEK2 and AURKA in Cancers

et al. 2020

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Tumor heterogeneity attributes substantial challenges in determining the treatment regimen. Along with the conventional treatment, such as chemotherapy and radiotherapy, targeted therapy has greater impact in cancer management. Owing to the recent advancements in proteomics, we aimed to mine and re-interrogate the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data sets which contain deep scale, mass spectrometry (MS)-based proteomic and phosphoproteomic data sets conducted on human tumor samples. Quantitative proteomic and phosphoproteomic data sets of tumor samples were explored and downloaded from the CPTAC database for six different cancers types (breast cancer, clear cell renal cell carcinoma (CCRCC), colon cancer, lung adenocarcinoma (LUAD), ovarian cancer, and uterine corpus endometrial carcinoma (UCEC)). We identified 880 phosphopeptide signatures for differentially regulated phosphorylation sites across five cancer types (breast cancer, colon cancer, LUAD, ovarian cancer, and UCEC). We identified the cell cycle to be aberrantly activated across these cancers. The correlation of proteomic and phosphoproteomic data sets identified changes in the phosphorylation of 12 kinases with unchanged expression levels. We further investigated phosphopeptide signature across five cancer types which led to the prediction of aurora kinase A (AURKA) and kinases-serine/threonine-protein kinase Nek2 (NEK2) as the most activated kinases targets. The drug designed for these kinases could be repurposed for treatment across cancer types.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Global Proteomic and Phosphoproteomic Data Sets Revealed Activation of NEK2 and AURKA in Cancers

et al. 2020

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“…As seen in Fig. 4, CDK4 encodes cyclin-dependent kinase 4, which, along with functional homolog CDK6 and family member CDK2, regulates cell-cycle G1 phase progression and G1/S transition [24,25]. Amplification of the chromosomal region that includes CDK4 has been reported in multiple cancer types [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors

Necchi

Bratslavsky

Shapiro

et al. 2019

European Urology Focus

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Background: Metastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy. Objective: To perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets. Design, setting, and participants: Ten patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture-based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Intervention: CGP on tumor samples. Outcome measurements and statistical analysis: Descriptive analyses and differences between histological subgroups were reported. Results and limitations: In these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of !10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses. Conclusions: Rare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies. Patient summary: Genomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.

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“…In this way, the genomic instability from chromosome segregation defects is protected by SAC. Once the SAC is passed, the APC/C E3 ligase complex stimulates and tags cyclin B and securin for ubiquitin-mediated degradation, leading to the initiation of mitosis [5]. In a word, the checkpoints offer a failsafe mechanism to ensure the genomic integrity from the parental cell to daughter cell.…”

Section: The Roles Of Cdks In the Cell Cyclementioning

confidence: 99%

“…However, TNBC is highly sensitive to a CDK2/9 inhibitor based on a preclinical trial, indicating that there may be unknown factors involving the CDK complex in TNBC proliferation [109]. On the other hand, some studies recently indicated that the expression of multiple genes of SAC is altered in TNBC, such as TTK, BUB1, MAD2, aurora kinase B (AURKB), and DNA repair proteins, presumably due to the highly genomic instability in TNBC [5].…”

Section: Dysregulation Of Cdks In Bcmentioning

confidence: 99%

“…The mammalian cell division and death are the two major predominant physiologic processes in the tissue homeostasis. The cell-cycle process is highly conserved and precisely controlled to govern the genome duplication and cell cycle, consisting of four distinct ordered phases, termed G0/G1 (gap 1), S (DNA synthesis), G2 (gap 2), and M (mitosis), and multiple checkpoints to ensure faithful replication in the S phase and the exact aggregation of the chromosomes into daughter cells [5]. The G1 and G2 phases are critical regulatory checkpoints, whereby the restriction point between the G1 and S phase determines whether the cells enter the S phase or exit the cell cycle to halt at the G0 phase.…”

Section: Introductionmentioning

confidence: 99%

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The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

380

216

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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

Cited by 133 publications

References 102 publications

Bioinformatics Analysis of Global Proteomic and Phosphoproteomic Data Sets Revealed Activation of NEK2 and AURKA in Cancers

Bioinformatics Analysis of Global Proteomic and Phosphoproteomic Data Sets Revealed Activation of NEK2 and AURKA in Cancers

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

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