On the Rise of Cyclin-Dependent Kinase Inhibitors in Breast Cancer: Progress & Ongoing Challenges.
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ABSTRACT:
SUBMITTER: Makhlin I
PROVIDER: S-EPMC8409318 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
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Project description:Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response.
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Project description:In cell development, the cell cycle is crucial, and the cycle progression's main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy's effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.
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Project description:Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
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Project description:Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.
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Project description:Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.
| S-EPMC8773807 | biostudies-literature
Project description:Cyclin-dependent kinase 9 (CDK9) plays a vital role in transcription through regulation of short-lived anti-apoptotic genes required for cancer cell survival. Therefore, targeting CDK9 with small molecule inhibitors has emerged as a potential cancer therapy. This article reviews the most recent CDK9 patent literature (2012-2020) related to small molecule inhibitors in cancer along with their selectivity profile and biological results in preclinical studies.
| S-EPMC7919902 | biostudies-literature
Project description:Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the preferred regimen for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer. However, the optimal treatment sequencing for CDK4/6i with other available therapeutic options is unclear. We conducted a targeted literature review to identify the current evidence on CDK4/6i treatment patterns in patients with breast cancer. The search was initially conducted in October 2021 and subsequently updated in October 2022. Biomedical databases and gray literature were searched, and bibliographies of included reviews were screened for relevant studies. The search identified ten reviews published since 2021 and 87 clinical trials or observational studies published since 2015. The included reviews discussed CDK4/6i usage with or without endocrine therapy (ET) in first-line and second-line treatment for patients with HR+/HER2- advanced or metastatic breast cancer, followed by ET, chemotherapy, or targeted therapy with ET. Clinical studies reported similar treatment sequences consisting of ET, chemotherapy, or targeted therapy with ET prior to CDK4/6i with ET, followed by ET monotherapy, chemotherapy, targeted therapy with ET, or continued CDK4/6i with ET. Current evidence suggests CDK4/6i are effective for HR+/HER2- advanced or metastatic breast cancer in earlier lines of therapy. Efficacy of CDK4/6i as measured by progression-free survival and overall survival was similar within a line of therapy regardless of the type of prior therapy. Survival on different post-CDK4/6i treatments was also similar within the same line of therapy. Additional research is needed to investigate the optimal place in therapy of CDK4/6i and the sequencing of treatments following progression on CDK4/6i.
| S-EPMC10191980 | biostudies-literature
Project description:Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.
| S-EPMC10356048 | biostudies-literature
Project description:Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1. Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response. Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.
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