Real-World Data with CDK4/6 Inhibitors—A Single Center Experience from Croatia DOI Open Access
Iva Skočilić, Marin Golčić, Ana Marija Bukovica

et al.

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(9), P. 895 - 895

Published: Aug. 23, 2024

Background: There are limited real-world data (RWD) regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in western Balkan. The aim our study was thus to analyze factors influencing progression-free survival (PFS) and overall (OS), along with differences adverse effects CDK therapy a tertiary healthcare center Croatia. Methods: We evaluated medical demographic for 163 consecutive patients metastatic breast cancer treated CDK4/6 at least one month, from October 2018, after drug became available Eligible were those who palbociclib, ribociclib, or abemaciclib. Results: median PFS treatment 2.2 years (95% CI 1.8–3.3), longest ongoing 5.4 years. Treatment first line associated longer compared second beyond (HR 0.50, 95% 0.3–0.9), without liver metastasis exhibited 0.46, 0.2–0.8) (both p < 0.05). Regarding choice inhibitors, ribociclib palbociclib 0.49, 0.29–0.82) (p = 0.0032), although effect not statistically significant when separating first-line 0.59, 0.29–1.2), second- later-line (0.49, 0.15–1.55); trend present both lines, however. presence 0.04), initial luminal A grade 0.039), time up 5 0.002) only that remained multivariate analysis. Median OS since diagnosis disease 4.5 3.9–6.3), start 3.7 3.4–4.4), while 15.8 13.8–18.3). no difference based on inhibitor 0.44) adjuvant hormonal 0.12), nonsignificant better regardless whether it first- second/later-line therapies > In analysis, 0.0003) under primary 0.03) worse OS. Conclusions: Our provides RWD HR+/HER2− cancer. To best knowledge, there Balkan; thus, valuable everyday clinical practice this region Europe, bridging gap between randomized trials reality

Language: Английский

Efficacy and Safety of CDK4/6 Inhibitors: A Focus on HR+/HER2− Early Breast Cancer DOI Creative Commons

Eva Valentina Klocker,

Daniel Egle,

Rupert Bartsch

et al.

Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone-receptor positive (HR+), HER2 negative (HER2−) metastatic breast cancer, and are now also established agents in high-risk intermediate-risk HR+ early cancer. Several strategies regarding CDK4/6i combinations or continuation beyond progression been successfully evaluated setting, considered a standard care. Mechanism action resistance mechanisms against addition to endocrine represent an important research topic, for Clinically, efficient substances that usually well tolerated. However, side effects differing between reported, might lead discontinuation, including disease setting. In adjuvant palbociclib has not improved outcomes, whereas large randomized phase III trials demonstrated significant disease-free survival benefit ribociclib (NATALEE trial) abemaciclib (monarchE trial). Patient selection, duration, backbone therapy, other study details differ these pivotal trials. This review focuses on both scientific background as all available clinical data CDK4/6i, with particular emphasis their use

Language: Английский

Citations

1
Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study DOI
Komal Jhaveri, Elgene Lim, Rinath Jeselsohn

et al.

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(35), P. 4173 - 4186

Published: Sept. 6, 2024

Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in

Language: Английский

Citations

4
Complete and Durable Remission in Metastatic Breast Cancer with Liver Metastases Using a Combination of Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor: What About Therapeutic De-Escalation? DOI

Choukri Elm’hadi,

Meryem Zerrik,

Rachid Tanz

et al.

Indian Journal of Gynecologic Oncology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 8, 2025

Language: Английский

Citations

0
Acral Melanoma: A Review of Its Pathogenesis, Progression, and Management DOI Creative Commons
Soo Hyun Kim,

Hensin Tsao

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 120 - 120

Published: Jan. 14, 2025

Acral melanoma is a distinct subtype of cutaneous malignant that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin the palms, soles, and nail beds. While acral only accounts for 2–3% all melanomas, it represents most common among darker-skinned, non-Caucasian individuals. Unlike other does not arise from UV radiation exposure accordingly associated with relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, epigenomic sequencing have revealed genetic alterations unique to melanoma, including novel driver genes, high copy number variations, complex chromosomal rearrangements. This review synthesizes current knowledge clinical features, epidemiology, treatment approaches focus pathogenesis gives rise its landscape. These findings highlight need deepen our molecular understanding better target this challenging melanoma.

Language: Английский

Citations

0
Discrete vulnerability to pharmacological CDK2 inhibition is governed by heterogeneity of the cancer cell cycle DOI Creative Commons
Vishnu Kumarasamy, Jianxin Wang,

Michelle Roti

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 9, 2025

Abstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 undergo G1 arrest following inhibition. The expression P16INK4A cyclin E1 determines this sensitivity to co-expression these genes occurs in breast patients highlighting their clinical significance as predictive biomarkers CDK2-targeted therapies. In genetically independent CDK2, pharmacological inhibitors suppress proliferation by inducing 4N increasing the expressions phospho-CDK1 (Y15) B1. CRISPR screens identify loss a mediator resistance inhibitor, INX-315. Furthermore, deletion reverses G2/M block induced restores proliferation. Complementary drug define multiple means cooperate with inhibition beyond G1/S. These include depletion mitotic regulators well CDK4/6 phases cycle. Overall, study underscores two fundamentally distinct features response conditioned context could serve basis differential therapeutic strategies wide range cancers.

Language: Английский

Citations

0
Targeting CDK4/6 in breast cancer DOI Creative Commons

Anusha Shanabag,

Jessica Armand,

Eugene Son

et al.

Experimental & Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Abstract Dysregulation of the cell cycle machinery, particularly overactivation cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark breast cancer pathogenesis. The introduction CDK4/6 inhibitors has transformed treatment landscape for hormone receptor-positive by effectively targeting abnormal progression. However, despite their initial clinical success, drug resistance remains significant challenge, with no reliable biomarkers available to predict response or guide strategies managing resistant populations. Consequently, numerous studies have sought investigate mechanisms driving optimize therapeutic use improve patient outcomes. Here we examine molecular regulating cycle, current applications in cancer, key contributing resistance. Furthermore, discuss emerging predictive highlight potential directions overcoming enhancing efficacy.

Language: Английский

Citations

0
Comprehensive pharmacokinetic profiling and molecular docking analysis of natural bioactive compounds targeting oncogenic biomarkers in breast cancer DOI Creative Commons

Basim Othman,

Saba Beigh,

Mohammad Albanghali

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 13, 2025

Breast cancer is one of the leading causes death in women worldwide, highlighting crucial need for novel and effective treatments. In this study, we look at ability four natural compounds i.e. Berberine, Curcumin, Withaferin A, Ellagic Acid to target important breast biomarkers such as B-cell lymphoma 2 (BCL-2), programmed death-ligand 1 (PDL-1), cyclin-dependent kinase 4/6 (CDK4/6) fibroblast growth factor receptor (FGFR). These indicators have roles tumor development, survival, immune response, cell cycle control, making them potential targets future Our study employs a variety techniques, including pharmacokinetic profiling (ADME), molecular docking, dynamics simulations, determine how successful these drugs could be therapy. The investigation found that Berberine stand out due their high absorption solubility, implying they suitable clinical application. When ran docking discovered substantial connections between chemicals proteins. Additionally, has binding affinity - 9.3 kcal/mol BCL-2, indicating it can impair protein's cell-protective activities. Acid, on other hand, an even higher PDL-1 9.8 kcal/mol, showing may able increase responses against tumors. Molecular simulations over 100 ns demonstrated stability protein-ligand complexes. Interestingly, was more structurally stable than throughout simulations. We consistent interactions key residues For example, (CID: 5281855) established persistent linkages with LYS43, ASP163, VAL27, whereas 2353) interacted ALA41, LEU152 simulation. conclusion, combination good pharmacokinetics, robust biomarkers, complexes makes interesting candidates further inhibitors treatment. findings establish framework research into inventive techniques effectively combating cancer.

Language: Английский

Citations

0
Physiologically Based Pharmacokinetic Model of Plasma and Intracranial Pharmacokinetics and CDK4/6 Occupancy of Abemaciclib to Optimizing Dosing Regimen for Brain Metastatic Patients DOI Creative Commons

Chao Zhang,

Shan Li, Jiawei Ren

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: 10(9), P. 9245 - 9256

Published: Feb. 24, 2025

Objective: The study aimed to develop a physiologically based pharmacokinetic (PBPK) model predict steady state trough concentrations (Cmin) and CDK4/6 occupancy in plasma cerebrospinal fluid (CSF) for abemaciclib (ABE) its three active metabolites. Additionally, biomarker was constructed simulate changes pRB TOPO-IIα expression. Methods: population PBPK models of ABE were developed using physicochemical, pharmacokinetics (PK), occupancy, biomarker, physiological properties. These then validated four clinical PK studies, two CSF one clinically observed expression change patients. Results: showed good consistency with data, most prediction-to-observation ratios falling within the range 0.5 2.0 AUC, Cmax, Cmin CSF. Key factors affecting total analytes (sum metabolites) identified as CYP3A4, ABCB1, ABCG2 expression, albumin levels. simulations suggested that optimal dosing regimen brain metastatic breast cancer (MBC) is either 150 or 200 mg twice daily (BID). Conclusions: successfully simulated profiles metabolites CSD, determined MBC. Overall,The can provide important insights personalized strategies, contributing improved treatment efficacy safety patients, particularly those

Language: Английский

Citations

0
Cyclin-Dependent Kinase Inhibition in Prostate Cancer: Past, Present, and Future DOI Open Access
Matthew Siskin, Minas P. Economides, David R. Wise

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 774 - 774

Published: Feb. 24, 2025

Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment hormone receptor-positive breast cancer, undergoing extensive testing as monotherapy and in various combinations potentially valuable modality patients. Thus far, limited number these studies have published results, been largely disappointing. In this review, we describe biologic rationale use CDK4/6 inhibitors existing clinical data describing their ongoing trials combination cancer. particular, focus on possible resistance mechanisms that may be particularly relevant patients, to de novo acquired resistance, highlight novel strategies can overcome resistance. Current actively working (1) refine role patients; (2) develop new other cell-cycle targets, such CDK2 CDK7; (3) explore therapies with pathways, PI3K or MAPK. Further genomic subtyping advanced will likely shed light subsets patients most benefit from cell-cycle-targeted agents.

Language: Английский

Citations

0
Advances in CDK4 and 6 Inhibitors: Transforming Breast Cancer Treatment DOI Open Access

Sonia Santander Ballestín,

María Abadía Labena,

Ana Avedillo-Salas

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 760 - 760

Published: Feb. 24, 2025

Breast cancer is the most common malignant neoplasm worldwide and prevalent one among women. It represents leading cause of cancer-related death females. Cyclin-dependent kinase 4 6 inhibitors disrupt cell cycle, inducing cellular senescence and, ultimately, apoptosis. Consequently, they have become a novel type adjuvant therapy for treatment advanced or metastatic breast characterised by positive hormone receptors human epidermal growth factor receptor 2 (HER-2) negative. A systematic review was conducted, analysing available literature on cyclin-dependent published over last five years. The aim to evaluate efficacy safety adding these drugs standard endocrine this pathology. combination with shown improve progression-free survival, overall chemotherapy-free intervals in patients who received therapy. addition CDK4/6 HER-2 negative significantly improved PFS, median compared use hormonal treatments alone placebo. Currently, are becoming established as new pathology, offering lower toxicity than chemotherapy. However, it necessary deeply investigate mechanisms resistance develop effective therapies overcome them.

Language: Английский

Citations

0