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

2020 ◽  
Vol 21 (6) ◽  
pp. 1960 ◽  
Author(s):  
Lei Ding ◽  
Jiaqi Cao ◽  
Wen Lin ◽  
Hongjian Chen ◽  
Xianhui Xiong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Metastatic Breast ◽  
Therapeutic Strategies ◽  
Cell Cycle Checkpoints ◽  
Cdk Inhibitors ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Hormone Receptor Positive

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.

EPR19-73: Risk of Gastrointestinal and Hepatic Toxicities in Patients With Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Treated With CDK4/6 Inhibitors

2019 ◽  
Vol 17 (3.5) ◽  
pp. EPR19-73
Author(s):  
Anita Sultan ◽  
Sriman Swarup ◽  
Somedeb Ball ◽  
Miguel Quirch ◽  
Meily Arevalo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Side Effects ◽  
Cell Cycle Progression ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Hormone Receptor Positive ◽  
Genes Encoding ◽  
Grade 3

Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.

scholarly journals Reversible Macrocytosis with Cyclin Dependent Kinase Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4882-4882
Author(s):  
Jasmine Kamboj ◽  
Elie Chalhoub ◽  
Peter E. Friedell
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Vitamin B12 ◽  
Hormone Receptor ◽  
Side Effect ◽  
Cell Cycle Progression ◽  
Endocrine Resistance ◽  
Cycle Progression ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Abstract Introduction Cyclin-dependant kinases (CDKs) are a family of serine threonine kinases regulating cell cycle progression. The interaction of cyclin D (encoded by CCND1) with CDK4/6 helps in hyper-phosphorylation of the retinoblastoma (Rb) gene product, which further facilitates in progression through G1 to S phase of the cell cycle. Oncogenic signals in Hormone Receptor(HR)-positive breast cancer facilitate CCND1 amplification and overexpression of CDK4/6 to drive breast cancer proliferation and are associated with endocrine resistance in breast cancer. CDK4/6 inhibitors selectively inhibit CDK4 and CDK6, resulting in loss of RB1 phosphorylation, henceforth blocking cell cycle progression and causing G1 phase arrest. These agents have profound activity in hormone receptor positive breast cancer cell lines and work synergistically with endocrine therapies to combat endocrine resistance in breast cancer. Neutropenia is a known side effect of CDK4/6 inhibitors, with an incidence as high as 70%. Anemia as a side effect has been reported with low incidence. We report macrocytosis in patients receiving CDK4/6 inhibitors. Methods Retrospective analysis was performed at Sanford Health Bemidji. IRB approval was sought prior to initiation of the review. All patients who received CDK4/6 inhibitor in combination with hormonal therapy from 1/2016-2/2018 were included. Dates for initiating CDK4/6 inhibitor, onset of macrocytosis, maximum mean corpuscular volume (MCV-max) achieved, correlation of time with rising MCV (MCV-t) and normalization of MCV in the absence of CDK4/6 inhibitor (reversibility of macrocytosis) was documented. Complete Blood Count (CBC) was reviewed. Work up for elevated MCV was performed in each patient. Bone marrow biopsies were not performed. Results Table. All patients (n=6) had rising MCV, within 4-6 weeks of initiation of the CDK4/6 inhibitor. Time to achieve MCV more than 100, varied from 3 to 7 months, this timing did not correlate well with baseline MCV. Progressively rising MCV with the duration of use of CDK4/6 inhibitor was seen. Reversibility of MCV was seen in 3 patients (Case B, C and D) who had interruption of CDK4/6 inhibitor for health related issues. Normalization of MCV on discontinuation of CDK4/6 inhibitor and rise in MCV on resumption of CDK4/6 inhibitor was seen. Hemoglobin drop from the baseline was not seen in any of the patients. Apart from neutropenia and macrocytosis, no other abnormality was seen on CBC. Stability of disease was documented in all patients on first set of scans done at 3 months and radiologic complete remission was documented in approximately 6-9 months of being on CDK4/6 inhibition. Macrocytosis workup was performed in all patients, including vitamin B12, folic acid, TSH, reticulocyte count, peripheral smear reviews and liver function tests. Vitamin B12 was low normal in case D, and was supplemented, without any changes seen on MCV. Conclusions CDK4/6 inhibition has become extremely prevalent in the recent times for hormone receptor positive breast cancer. We hypothesize that CDK4/6 inhibition produces reversible macrocytic anemia of unknown clinical significance. Given all patients had elevation in MCV along with complete radiologic remission, there is a possible causal relationship of elevated MCV and treatment response. The long-term clinical significance of observed macrocytosis and possible dysplasia, are important questions that need to be answered in large clinical trials. Disclosures No relevant conflicts of interest to declare.

Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells

2020 ◽  
Vol 177 (1) ◽  
pp. 226-234 ◽  
Author(s):  
Shuyan Lu ◽  
Tae Sung ◽  
Marina Amaro ◽  
Brad Hirakawa ◽  
Bart Jessen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Progression ◽  
Intestinal Epithelial Cells ◽  
Intestinal Cell ◽  
Cdk Inhibitors ◽  
Intestinal Epithelial ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
The Impact

Abstract Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. In addition, collateral damage to highly proliferative normal cells by CDK inhibitors remains a safety concern. Intestinal epithelial cells are highly proliferative and the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. Using the rat intestinal epithelial (IEC6) cells as an in vitro model, we found that the selective CDK4/6 inhibitor palbociclib lacked potent anti-proliferative activity in IEC6 relative to the breast cancer cell line MCF7, indicating the absence of intestinal cell reliance on CDK4/6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, we chose common targets of CDK inhibitors (CDK 1, 2, 4, 6, and 9) for targeted gene knockdown to evaluate phenotypes. Surprisingly, only CDK1 and CDK9 knockdown demonstrated profound cell death or had moderate growth effects, respectively. CDK2, 4, or 6 knockdowns, whether single, double, or triple combinations, did not have substantial impact. Studies evaluating CDK1 knockdown under various cell seeding densities indicate direct effects on viability independent of proliferation state and imply a potential noncanonical role for CDK1 in intestinal epithelial biology. This research supports the concept that CDK1 and CDK9, but not CDKs 2, 4, or 6, are essential for intestinal cell cycle progression and provides safety confidence for interphase CDK inhibition.

scholarly journals Antioestrogen-mediated cell cycle arrest and apoptosis induction in breast cancer and multiple myeloma cells

2008 ◽  
Vol 40 (3) ◽  
pp. 101-112 ◽  
Author(s):  
Jack-Michel Renoir ◽  
Céline Bouclier ◽  
Amélie Seguin ◽  
Véronique Marsaud ◽  
Brigitte Sola
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Cycle Progression ◽  
Therapeutic Strategies ◽  
Apoptosis Induction ◽  
Rational Basis ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Inhibit Cell Cycle Progression

Antioestrogens (AEs) are synthetic molecules that block proliferation and induce apoptosis in breast cancer (BC) cells, principally by competing with oestradiol for binding to oestrogen receptors. Their antiproliferative activity and their pro-apoptotic capacity are well documented and a small number of molecules of this class are currently used clinically for the treatment of BC. AEs also inhibit cell cycle progression and/or induce apoptosis in multiple myeloma (MM) cells. Encouraging preliminary results have been obtained with patients and on xenografts with MM, providing a rational basis for the clinical use of AEs. This review focuses on antioestrogen-mediated signalling for blocking targets involved in the cell cycle, survival and apoptosis in both BC and MM cells. Improvement in our understanding of the mechanisms underlying the relationships between these compounds and their targets should lead to more beneficial therapeutic strategies.

Time to treatment failure of palbociclib and letrozole as second-line therapy or beyond in hormone receptor-positive advanced breast cancer

2018 ◽  
Vol 25 (6) ◽  
pp. 1374-1380 ◽  
Author(s):  
M Alexandra Schickli ◽  
Michael J Berger ◽  
Maryam Lustberg ◽  
Marilly Palettas ◽  
Craig A Vargo
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Treatment Failure ◽  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Second Line ◽  
Time To Treatment ◽  
Cyclin Dependent Kinases ◽  
Hormone Receptor Positive ◽  
Time To Treatment Failure

Purpose The management of endocrine therapy resistance is one of the most challenging facets of advanced breast cancer treatment. Palbociclib is an inhibitor of cyclin-dependent kinases 4 and 6 approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with fulvestrant in postmenopausal women with disease progression following endocrine therapy. However, treatment responsiveness of tumors to palbociclib after multiple lines of endocrine therapy is not clearly established. The purpose of this study was to determine the efficacy of palbociclib and letrozole in patients pretreated with one or more lines of endocrine therapy. Methods This was a single-center, retrospective cohort study of all postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer patients who received palbociclib and letrozole as a second-line endocrine therapy or beyond (and no prior cyclin-dependent kinases 4 and 6 inhibitor therapy) between February 1, 2015, and July 31, 2016. The primary objective was to evaluate time to treatment failure of palbociclib in combination with letrozole as a second-line of therapy or beyond. Results Fifty-three patients meeting eligibility criteria were included in the analysis. For the primary outcome, the median time to treatment failure of palbociclib and letrozole was 6.3 months (95% CI 3.1–7.4 months). Progression-free survival of palbociclib and letrozole therapy was 6.4 months (95% CI 4.9–8.3 months). Conclusions Palbociclib and letrozole therapy is a viable, effective treatment option for metastatic breast cancer patients who were not exposed to cyclin-dependent kinases 4 and 6 inhibitors as a first-line endocrine therapy. The benefits of palbociclib and letrozole therapy were seen without excessive toxicity, and although neutropenia was common, it may be managed with dose reduction.

scholarly journals Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

2020 ◽  
Author(s):  
Wenbao Lu ◽  
Meicen Zhou ◽  
Bing Wang ◽  
Xueting Liu ◽  
Bingwei Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

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