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Expert Opinion on Investigational Drugs Sep 2014Cyclin-dependent kinases (CDK) represent attractive targets in oncology due to their key role in controlling gene transcription and cell cycle progression. Dinaciclib... (Review)
Review
INTRODUCTION
Cyclin-dependent kinases (CDK) represent attractive targets in oncology due to their key role in controlling gene transcription and cell cycle progression. Dinaciclib (MK-7965, formerly SCH727965) is a relatively novel CDK 1/2/5/9 inhibitor that has shown promising results in preclinical studies and an acceptable safety profile in Phase I clinical trials. It is currently under clinical evaluation for the treatment of hematological and solid malignancies, including breast cancer.
AREAS COVERED
This review summarizes the current understanding of CDK's role in physiology and cancer, and the therapeutic value of blocking their pathways in breast cancer. Particularly, the article reviews the preclinical and clinical data for dinaciclib in its use for the treatment of breast cancer.
EXPERT OPINION
A better understanding of the molecular mechanisms underlying cell cycle dysregulation in cancer is needed in order to develop novel CDK inhibitors. Additionally, further efforts are needed to identify potential biomarkers of dinaciclib efficacy, which could allow a better selection of patients enrolled in clinical trials. Moreover, combination therapies with dinaciclib or other CDK and chemotherapy, endocrine therapy or targeted therapies might be further evaluated in breast cancer patients.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cyclic N-Oxides; Cyclin-Dependent Kinases; Drug Design; Female; Humans; Indolizines; Patient Selection; Pyridinium Compounds
PubMed: 25107301
DOI: 10.1517/13543784.2014.948152 -
Cancers Mar 2021Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year...
Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II-IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.
PubMed: 33800911
DOI: 10.3390/cancers13051135 -
Haematologica May 2023Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and...
Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.
Topics: Humans; Animals; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Cell Line, Tumor; Apoptosis; Proto-Oncogene Proteins c-bcl-2; Bridged Bicyclo Compounds, Heterocyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents
PubMed: 36700399
DOI: 10.3324/haematol.2022.281443 -
Frontiers in Oncology 2022Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the...
BACKGROUND
Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC.
AIM
The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility.
METHODS
The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study.
RESULTS AND CONCLUSIONS
Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.
PubMed: 36505806
DOI: 10.3389/fonc.2022.1014280 -
Scientific Reports Oct 2020Cholangiocarcinoma (CCA) is a highly invasive cancer, diagnosed at an advanced stage, and refractory to surgical intervention and chemotherapy. Cyclin-dependent kinases...
Cholangiocarcinoma (CCA) is a highly invasive cancer, diagnosed at an advanced stage, and refractory to surgical intervention and chemotherapy. Cyclin-dependent kinases (CDKs) regulate cell cycle progression and transcriptional processes, and are considered potential therapeutic targets for cancer. Dinaciclib is a small molecule multi-CDK inhibitor targeting CDK 2/5/9. In this study, the therapeutic efficacy of dinaciclib was assessed using patient-derived xenograft cells (PDXC) and CCA cell lines. Treatment with dinaciclib significantly suppressed cell proliferation, induced caspase 3/7 levels and apoptotic activity in PDXC and CCA cell lines. Dinaciclib suppressed expression of its molecular targets CDK2/5/9, and anti-apoptotic BCL-XL and BCL2 proteins. Despite the presence of cyclin D1 amplification in the PDXC line, palbociclib treatment had no effect on cell proliferation, cell cycle or apoptosis in the PDXC as well as other CCA cell lines. Importantly, dinaciclib, in combination with gemcitabine, produced a robust and sustained inhibition of tumor progression in vivo in a PDX mouse model, greater than either of the treatments alone. Expression levels of two proliferative markers, phospho-histone H3 and Ki-67, were substantially suppressed in samples treated with the combination regimen. Our results identify dinaciclib as a novel and potent therapeutic agent alone or in combination with gemcitabine for the treatment of CCA.
Topics: Animals; Apoptosis; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinase 9; Deoxycytidine; Gastrointestinal Neoplasms; Histones; Humans; Indolizines; Inhibitory Concentration 50; Ki-67 Antigen; Male; Mice; Mice, Inbred NOD; Proto-Oncogene Proteins c-bcl-2; Pyridinium Compounds; Xenograft Model Antitumor Assays; bcl-X Protein; Gemcitabine
PubMed: 33116269
DOI: 10.1038/s41598-020-75578-5 -
Blood Advances Aug 2019Dinaciclib enhances NK-cell activity against leukemia cells in preclinical AML models. Enhanced NK-cell activation by dinaciclib-treated AML is associated with...
Dinaciclib enhances NK-cell activity against leukemia cells in preclinical AML models. Enhanced NK-cell activation by dinaciclib-treated AML is associated with downregulation of inhibitory NK ligand HLA-E on leukemia cells.
Topics: Animals; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclic N-Oxides; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Immunomodulation; Immunophenotyping; Indolizines; Killer Cells, Natural; Leukemia, Myeloid, Acute; Lymphocyte Activation; Mice; Protein Kinase Inhibitors; Pyridinium Compounds; Xenograft Model Antitumor Assays
PubMed: 31416822
DOI: 10.1182/bloodadvances.2019000064 -
Molecular Oncology Dec 2023A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological...
A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib-based combinations with B-cell lymphoma 2 or B-cell lymphoma extra-large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL-1). Simultaneous treatment with dinaciclib and BH3 mimetics ABT-199 or A-1155463 additionally showed a synergistic effect in plasma cells from MM patients, ex vivo. Altered MM cytogenetics did not affect dinaciclib response ex vivo, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin-dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL-1.
Topics: Humans; Myeloid Cell Leukemia Sequence 1 Protein; Cell Line, Tumor; Plasma Cells; Multiple Myeloma; Apoptosis; Proto-Oncogene Proteins c-bcl-2; bcl-X Protein; Antineoplastic Agents
PubMed: 37704591
DOI: 10.1002/1878-0261.13522 -
American Journal of Cancer Research 2021Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division... (Review)
Review
Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.
PubMed: 34094661
DOI: No ID Found -
Oncology Reports May 2022Cyclin‑dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy are the current standard of care used in the first‑line treatment of hormone...
Cyclin‑dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy are the current standard of care used in the first‑line treatment of hormone receptor‑positive/HER2‑negative metastatic breast cancer (BC). Although CDK4/6 inhibitors mainly target the cell cycle, emerging evidence has indicated further potential roles of CDKs other than regulating cell cycle progression. The G and G/M transition regulators, including cyclins D and E, as well as their catalytic partners, CDK2, CDK4 and CDK6, have been reported to play crucial roles in pluripotency maintenance and cell fate decisions of human pluripotent stem cells by controlling transcription factors, signaling pathways and epigenetic regulators. Dinaciclib, a CDK1/2/5/9 inhibitor, is currently being evaluated in clinical trials against various cancer types, including BC. However, the underlying molecular mechanisms of CDK1/2/5/9 inhibitors in regulating BC stemness remain poorly understood. The present study aimed to examine the stemness‑inhibitory effects of dinaciclib in MCF‑7 (luminal) and HCC‑1806 (triple‑negative) BC cells. We found that this drug not only effectively reduced the self‑renewal abilities and other malignant properties, but also dose‑dependently decreased the protein expression levels of three BC stem cell markers, CD44, aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and BMI1 proto‑oncogene, polycomb ring finger (Bmi1), as well as three embryonic stem cell markers, Oct4, Nanog and Sox2. Moreover, the dinaciclib‑induced decrease of Oct4 and Nanog protein expression was able to be restored by co‑treatment with MG‑132, a proteasome inhibitor. Forkhead box M1 (FoxM1), both a stemness‑stimulating transcription factor and a cell cycle regulator, along with the Hedgehog signaling pathway, were identified as the therapeutic targets of dinaciclib. Collectively, the present results demonstrated a novel role of dinaciclib in suppressing BC stemness and indicated its potential use for future cancer treatments.
Topics: Breast Neoplasms; Cell Line, Tumor; Cyclic N-Oxides; Female; Forkhead Box Protein M1; Hedgehog Proteins; Humans; Indolizines; Neoplastic Stem Cells; Pyridinium Compounds
PubMed: 35417031
DOI: 10.3892/or.2022.8316 -
Anti-cancer Drugs Feb 2024Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further...
Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing β-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating β-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.
Topics: Humans; Mice; Animals; beta Catenin; Catenins; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Proliferation; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Cell Movement
PubMed: 37694833
DOI: 10.1097/CAD.0000000000001545