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Keywords = cyclin-dependent kinase 6

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20 pages, 1400 KiB  
Review
Novel Therapeutics and the Path Toward Effective Immunotherapy in Malignant Peripheral Nerve Sheath Tumors
by Joshua J. Lingo, Elizabeth C. Elias and Dawn E. Quelle
Cancers 2025, 17(14), 2410; https://doi.org/10.3390/cancers17142410 - 21 Jul 2025
Viewed by 460
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor [...] Read more.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy. Full article
(This article belongs to the Special Issue Next-Generation Cancer Therapies)
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19 pages, 9060 KiB  
Article
Targeting CDK4/6 in Cancer: Molecular Docking and Cytotoxic Evaluation of Thottea siliquosa Root Extract
by Maruthamuthu Rathinam Elakkiya, Mohandas Krishnasreya, Sureshkumar Tharani, Muthukrishnan Arun, L. Vijayalakshmi, Jiseok Lim, Ayman A. Ghfar and Balasundaramsaraswathy Chithradevi
Biomedicines 2025, 13(7), 1658; https://doi.org/10.3390/biomedicines13071658 - 7 Jul 2025
Viewed by 426
Abstract
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. [...] Read more.
Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) are pivotal regulators of the cell cycle, whose dysregulation is closely linked to cancer progression. While synthetic CDK4/6 inhibitors such as Palbociclib and Ribociclib are clinically effective, their use is limited by significant adverse effects. Methods: In this study, the aqueous root extract of Thottea siliquosa, a traditionally used medicinal plant, was evaluated for its potential as a natural CDK4/6 inhibitor. Phytochemical profiling using GC-MS identified bioactive compounds, which were subsequently subjected to molecular docking, ADME prediction, and in vitro cell-based assays using HCT116 and L929 cells. Results: The docking results revealed that Isocorydine (−7.4 kcal/mol for CDK4 and −7.2 kcal/mol for CDK6) and Thunbergol (−6.5 kcal/mol for CDK4 and −7.0 kcal/mol for CDK6) exhibited promising binding affinities comparable to standard CDK inhibitors, Palbociclib (−7.2, −8.3 kcal/mol) and Ribociclib (−7.1, −8.1 kcal/mol). Among the other tested natural compounds, Squalene (−7.1 kcal/mol for CDK4) and 2-palmitoylglycerol (−5.2 kcal/mol for CDK4, −4.9 kcal/mol for CDK6) demonstrated moderate binding affinities. ADME analysis confirmed favorable drug-like properties with minimal toxicity alerts. The extract displayed dose-dependent cytotoxicity with an IC50 of 140 μg/mL and reduced cell migration in HCT116 cells, indicating potential anti-proliferative effects. These findings suggest that T. siliquosa root extract, through synergistic phytochemical interactions, holds promise as a multi-targeted, plant-based therapeutic candidate for CDK4/6-associated cancers, warranting further in vitro and in vivo validation. Full article
(This article belongs to the Special Issue Progress in Cytotoxicity of Biomaterials)
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18 pages, 2254 KiB  
Article
Didemnosides A and B: Antiproliferative Nucleosides from the Red Sea Marine Tunicate Didemnum Species
by Lamiaa A. Shaala, Diaa T. A. Youssef, Hadeel Almagthali, Ameen M. Almohammadi, Wafaa T. Arab, Torki Alzughaibi, Noor M. Bataweel and Reham S. Ibrahim
Mar. Drugs 2025, 23(7), 262; https://doi.org/10.3390/md23070262 - 23 Jun 2025
Viewed by 596
Abstract
Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides [...] Read more.
Marine tunicates are a very attractive and abundant source of secondary metabolites with chemical diversity and biological activity. Fractionation and purification of the organic extract of the Red Sea tunicate Didemnum species resulted in the isolation and identification of three new compounds, didemnosides A and B (1 and 2) and 1,1′,3,3′-bisuracil (3), together with thymidine (4), 2′-deoxyuridine (5), homarine (6), and acetamide (7). Planar structures of the compounds were explained through analyses of their 1D (1H and 13C) and 2D (1H–1H COSY, HSQC, and HMBC) NMR spectra and high-resolution mass spectral determinations. Compound 1 exhibited the highest growth inhibition toward the MCF-7 cancer cell line with IC50 values of 0.597 μM, while other compounds were inactive (≥50 μM) against this cell line. On the other hand, compounds 1, 2, and 47 moderately inhibited SW-1222 and PC-3 cells with IC50 values ranging between 5.25 and 9.36 μM. Molecular docking analyses of the top three active compounds on each tested cell line exposed stable interactions into the active pockets of estrogen receptor alpha (ESR1), human topoisomerase II alpha (TOP2A), and cyclin-dependent kinase 5 (CDK5) which are contemplated as essential targets in cancer treatments. Thus, compound 1 represents a scaffold for the development of more effective anticancer drugs. Full article
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14 pages, 966 KiB  
Article
Niraparib Plus Aromatase Inhibitors for Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with a Germline BRCA Mutation
by Laura Lema, José Manuel Pérez-García, Salvador Blanch, Judith Balmaña, José Ángel García-Sáenz, Elena Filipovich Vegas, Begoña Jiménez, Juan de la Haba, Marta Campolier, Eileen Shimizu, Daniel Alcalá-López, Miguel Sampayo-Cordero, Javier Cortés and Antonio Llombart-Cussac
Cancers 2025, 17(11), 1744; https://doi.org/10.3390/cancers17111744 - 22 May 2025
Viewed by 917
Abstract
Background: Niraparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor with promising activity for patients with advanced breast cancer harboring germline BRCA1/2 mutations. Methods: LUZERN (NCT04240106) was a multicenter, open-label, Simon’s two-stage, phase II clinical trial evaluating the efficacy and safety of [...] Read more.
Background: Niraparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor with promising activity for patients with advanced breast cancer harboring germline BRCA1/2 mutations. Methods: LUZERN (NCT04240106) was a multicenter, open-label, Simon’s two-stage, phase II clinical trial evaluating the efficacy and safety of niraparib with aromatase inhibitors (AIs) for patients with HR-positive/HER2-negative advanced breast cancer with either a germline BRCA1/2 mutation (cohort A) or germline BRCA1/2 wild-type and homologous recombination deficiency (exploratory cohort B). Eligible patients received ≤1 line of chemotherapy and 1–2 prior lines of endocrine therapy for advanced disease with secondary resistance to the last AI-based regimen. Patients received niraparib (300 mg or 200 mg) plus an AI. The primary endpoint was the clinical benefit rate (CBR) in cohort A. Results: Between June 2020 and November 2022, 14 patients were enrolled in cohort A (n = 6 for stage I, n = 8 for stage II) and no patients were enrolled in cohort B. One patient was excluded from the efficacy analysis due to no prior AI treatment. Nearly all patients (92.9%) previously received a cyclin-dependent kinase 4/6 inhibitor, but no patients had received prior platinum-based chemotherapy. Median follow-up was 16.7 months (range: 13.2–18.2). The CBR was 46.2% (95% CI: 19.2–74.9), meeting the primary endpoint. Median progression-free survival was 5.5 months (95% CI: 1.9–8.5), and median overall survival was 18.1 months (95% CI: 9.7–NE). The safety profile was consistent with the known toxicity of both drugs. Conclusions: Niraparib combined with an AI has encouraging antitumor activity and a manageable safety profile in patients with AI-resistant HR-positive/HER2-negative advanced breast cancer with germline BRCA1/2 mutations. Full article
(This article belongs to the Section Cancer Therapy)
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17 pages, 2200 KiB  
Article
The Clinical Outcomes and Safety of Sacituzumab Govitecan in Heavily Pretreated Metastatic Triple-Negative and HR+/HER2− Breast Cancer: A Multicenter Observational Study from Turkey
by Harun Muğlu, Kaan Helvacı, Bahadır Köylü, Mehmet Haluk Yücel, Özde Melisa Celayir, Umut Demirci, Başak Oyan Uluç, Gül Başaran, Taner Korkmaz, Fatih Selçukbiricik, Ömer Fatih Ölmez and Ahmet Bilici
Cancers 2025, 17(9), 1592; https://doi.org/10.3390/cancers17091592 - 7 May 2025
Viewed by 990
Abstract
Background/Objectives: Sacituzumab govitecan (SG) is an antibody–drug conjugate targeting Trop-2, approved for use in metastatic triple-negative breast cancer (mTNBC) and more recently in the hormone receptor-positive/HER2-negative (mHRPBC) subtype. While clinical trials have demonstrated its efficacy, real-world data—especially those involving both molecular subtypes—remain scarce. [...] Read more.
Background/Objectives: Sacituzumab govitecan (SG) is an antibody–drug conjugate targeting Trop-2, approved for use in metastatic triple-negative breast cancer (mTNBC) and more recently in the hormone receptor-positive/HER2-negative (mHRPBC) subtype. While clinical trials have demonstrated its efficacy, real-world data—especially those involving both molecular subtypes—remain scarce. This multicenter, retrospective study aimed to evaluate real-world observational data describing the clinical outcomes, safety, and prognostic factors associated with SG treatment in patients with mTNBC or mHRPBC. Methods: A total of 68 patients treated with SG between 2022 and 2025 were included from multiple oncology centers in Turkey. Patients with mTNBC were required to have received at least one prior chemotherapy line, while mHRPBC patients had received at least two prior chemotherapy lines in addition to cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6) plus hormone therapy. The clinical outcomes—including the progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)—were evaluated. Univariate and multivariate analyses were performed to identify factors influencing outcomes. Adverse events (AEs) were also documented and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5.0). Results: The cohort included 35 (51.5%) mTNBC and 33 (48.5%) mHRPBC patients. The median PFS was 6.1 months, and the median OS was 12.5 months, with no significant differences between subtypes. The ORR was 52.9%, with a complete response observed in 10.3% of patients. A high Eastern Cooperative Oncology Group Performance Status (ECOG PS) and liver metastasis were independent predictors of poorer PFS and OS. Prior immunotherapy did not negatively impact SG’s efficacy. SG was generally well tolerated; the most common AEs were alopecia, anemia, neutropenia, and diarrhea. Treatment discontinuation due to AEs was rare (2.9%). Conclusions: SG was associated with similar clinical outcomes and tolerability in both the mTNBC and mHRPBC subtypes. Although the real-world PFS and OS outcomes mirror those seen in clinical trials, the absence of a control group means that these findings should be interpreted descriptively rather than as confirmation of treatment efficacy. Importantly, this study provides one of the first real-world datasets evaluating SG in the mHRPBC subgroup, highlighting its potential role beyond clinical trials. These results support SG as a valuable therapeutic option in heavily pretreated patients, warranting further prospective and biomarker-driven studies. Full article
(This article belongs to the Section Cancer Therapy)
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25 pages, 2098 KiB  
Review
Mechanistic Roles of Transcriptional Cyclin-Dependent Kinases in Oncogenesis: Implications for Cancer Therapy
by Mohammed Alrouji, Mohammed S. Alshammari, Saleha Anwar, Kumar Venkatesan and Anas Shamsi
Cancers 2025, 17(9), 1554; https://doi.org/10.3390/cancers17091554 - 3 May 2025
Viewed by 1185
Abstract
Cyclin-dependent kinases (CDKs) are pivotal in regulating cell cycle progression and transcription, making them crucial targets in cancer research. The two types of CDKs that regulate different biological activities are transcription-associated CDKs (e.g., CDK7, 8, 9, 12, and 13) and cell cycle-associated CDKs [...] Read more.
Cyclin-dependent kinases (CDKs) are pivotal in regulating cell cycle progression and transcription, making them crucial targets in cancer research. The two types of CDKs that regulate different biological activities are transcription-associated CDKs (e.g., CDK7, 8, 9, 12, and 13) and cell cycle-associated CDKs (e.g., CDK1, 2, 4, and 6). One characteristic of cancer is the dysregulation of CDK activity, which results in unchecked cell division and tumor expansion. Targeting transcriptional CDKs, which control RNA polymerase II activity and gene expression essential for cancer cell survival, has shown promise as a therapeutic approach in recent research. While research into selective inhibitors for transcriptional CDKs is ongoing, inhibitors that target CDK4/6, such as palbociclib and ribociclib, have demonstrated encouraging outcomes in treating breast cancer. CDK7, CDK8, and CDK9 are desirable targets for therapy since they have shown oncogenic roles in a variety of cancer types, such as colorectal, ovarian, and breast malignancies. Even with significant advancements, creating selective inhibitors with negligible off-target effects is still difficult. This review highlights the need for more research to optimize therapeutic strategies and improve patient outcomes by giving a thorough overview of the non-transcriptional roles of CDKs in cancer biology, their therapeutic potential, and the difficulties in targeting these kinases for cancer treatment. Full article
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14 pages, 2385 KiB  
Article
CDC6 Inhibits CDK1 Activity in MII-Arrested Oocyte Cell-Free Extract
by Louis Dillac, Klaudia Porębska, Malgorzata Kloc, Rafal P. Piprek, Jean-Pierre Tassan and Jacek Z. Kubiak
Int. J. Mol. Sci. 2025, 26(9), 4309; https://doi.org/10.3390/ijms26094309 - 1 May 2025
Viewed by 675
Abstract
The control of cyclin-dependent kinase 1 (CDK1) kinase activity is crucial for cell cycle progression. Cell division cycle 6 (CDC6) inhibits this activity in embryonic mitoses, and thus regulates the timing of cell division progression. The meiotic cell cycle differs greatly from the [...] Read more.
The control of cyclin-dependent kinase 1 (CDK1) kinase activity is crucial for cell cycle progression. Cell division cycle 6 (CDC6) inhibits this activity in embryonic mitoses, and thus regulates the timing of cell division progression. The meiotic cell cycle differs greatly from the mitotic one. Metaphase II (MII)-arrested oocytes remain in prolonged M-phase state due to the high activity of CDK1 in the presence of CytoStatic Factor (CSF). The role of CDC6 in the control of CDK1 during MII and oocyte activation remains unknown. Here, we studied the role of CDC6/CDK1 interactions in Xenopus laevis cell-free extracts arrested in MII (CSF extract) and upon calcium activation leading to meiotic-to-mitotic transition. The CSF extract allows analysis of biochemical processes based on immunodepletion of selected proteins and facilitates manipulations using addition of recombinant proteins. We show by glutathione S-transferase (GST)-CDC6 pull-down that CDC6 associates with CDK1 in CSF extract and by histone H1 kinase assay that it downregulates CDK1 activity. Thus, CDC6-dependent inhibition of CDK1 is involved in the homeostasis of the MII-arrest. Upon CSF extract activation with calcium exogenous GST-CDC6 provokes accelerated transition from MII to interphase, while the depletion of endogenous CDC6 results in a slower transition to interphase. We demonstrate this by following both the phosphorylation state of CDK1 substrate cell division cycle 27 (CDC27) and histone H1 kinase assay. Importantly, increasing doses of GST-CDC6 proportionally accelerate CDK1 inactivation showing that CDC6 controls the dynamics of MII to interphase transition in a dose-dependent manner. Thus, CDC6 is a CDK1 silencer acting upon both the MII arrest and CSF extract activation by assuring the physiological activity of CDK1 during this meiotic arrest and correct timely inactivation of this kinase during the second process. Thus, we show that CDC6 controls CDK1 not only during mitotic divisions, but also in MII-arrest and the meiotic-to-mitotic transition in Xenopus laevis cell-free extracts. This study aims to bridge that gap by investigating CDC6 function using a biochemically controlled system. Full article
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37 pages, 1374 KiB  
Review
Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2− Breast Cancer
by Paola Ferrari, Maria Luisa Schiavone, Cristian Scatena and Andrea Nicolini
Int. J. Mol. Sci. 2025, 26(7), 3438; https://doi.org/10.3390/ijms26073438 - 7 Apr 2025
Viewed by 1693
Abstract
Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These [...] Read more.
Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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17 pages, 2589 KiB  
Article
Impact of Patient Profile on CDK4/6 Inhibitor Therapy Outcomes: A Real-World Data Analysis
by Ioana-Miruna Stanciu, Maria-Cristina Orlov-Slavu, Andreea-Ioana Parosanu and Cornelia Nitipir
Int. J. Mol. Sci. 2025, 26(7), 3357; https://doi.org/10.3390/ijms26073357 - 3 Apr 2025
Viewed by 1017
Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for patients with hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, their efficacy is influenced by various clinical and biological factors, including patient age, tumor biology, and treatment-related toxicities. The aim of [...] Read more.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the treatment landscape for patients with hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer. However, their efficacy is influenced by various clinical and biological factors, including patient age, tumor biology, and treatment-related toxicities. The aim of this study is to evaluate the impact of demographic, clinical, and tumor-related characteristics on the efficacy of CDK4/6 inhibitors in a cohort of patients with metastatic HR+/HER2− breast cancer. We conducted a retrospective cohort study analyzing the outcomes of 95 patients with metastatic ER-positive, HER2-negative breast cancer (BC) treated with CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) in combination with endocrine therapy. The patient demographics, tumor characteristics, and treatment regimens were examined, with a primary focus on progression-free survival (PFS), overall survival (OS), time on treatment (TOT), and the influence of clinical and biological factors. Younger patients (under 50 years) demonstrated higher tumor aggressiveness, reflected by higher Ki67 levels and histological grades, which negatively impacted their survival outcomes. Ribociclib was associated with the highest survival benefit, particularly in younger patients. Older patients (over 50 years) showed greater rates of comorbidities and toxicity, with dose reductions correlated with improved survival outcomes. This study highlights the significance of personalized treatment strategies based on patient age, comorbidities, and tumor biology. Ribociclib shows superior efficacy in younger, less comorbid patients, while palbociclib remains a viable option for older patients with higher comorbidity burdens. Full article
(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)
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29 pages, 2013 KiB  
Review
CDK4/6 as a Therapeutic Target in HR+/HER2− Breast Cancer Cells—Current Treatment Status
by Kamila Krupa, Anna Liszcz-Tymoszuk, Natalia Czerw, Aleksandra Czerw, Katarzyna Sygit, Remigiusz Kozłowski, Andrzej Deptała and Anna Badowska-Kozakiewicz
Cancers 2025, 17(6), 1039; https://doi.org/10.3390/cancers17061039 - 20 Mar 2025
Cited by 2 | Viewed by 2240
Abstract
Breast cancer is the most frequently diagnosed neoplasm in the world. It can be classified into four main subtypes, each of them showing differences in the expression of hormone receptor (HR), human epidermal growth factor receptor 2 (HER2), and in cell metabolism. Since [...] Read more.
Breast cancer is the most frequently diagnosed neoplasm in the world. It can be classified into four main subtypes, each of them showing differences in the expression of hormone receptor (HR), human epidermal growth factor receptor 2 (HER2), and in cell metabolism. Since 2015, when The U.S. Food and Drug Administration (FDA) approved the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that regulates the cell cycle, treatment of HR+/HER2− BC has become much more effective. Currently, palbociclib, ribociclib, and abemaciclib are more often used both in combination with endocrine therapy as well as in monotherapy. Their application has been extensively verified in many clinical trials such as PALOMA-1,2,3, MONALEESA-1,2,3,7, and MONARCH-1,2,3, which allowed the verification of differences in their effectiveness, dosage, and adverse effects. Subsequent studies, MonarchE and NATALEE, examined the role of these inhibitors as adjuvant therapy, as well as at verifying their safety. Moreover, dalpiciclib is being investigated in HR+/HER2− BC treatment. This article will summarize clinical efficacy, recommendations, and differences in toxicity profile between palbociclib, ribociclib, and abemaciclib and will also discuss the possibility of using dalpiciclib in the treatment of breast cancer. Full article
(This article belongs to the Section Molecular Cancer Biology)
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13 pages, 798 KiB  
Review
Efficiency of Fulvestrant Monotherapy After CDK4/6 Inhibitor Exposure: Is This a Viable Choice?
by Nanae Ogata, Brian G Barnett, Nicholas J. H. Sharp, Takeo Fujii, Toshiaki Iwase, Sandra E. Dunn and Naoto T. Ueno
Cancers 2025, 17(5), 884; https://doi.org/10.3390/cancers17050884 - 4 Mar 2025
Viewed by 2558
Abstract
Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies of a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following CDK4/6 inhibitor progression remains challenging, especially for tumors lacking actionable [...] Read more.
Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies of a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following CDK4/6 inhibitor progression remains challenging, especially for tumors lacking actionable mutations. Real-world data suggest that fulvestrant monotherapy is frequently selected in this post-CDK4/6 inhibitor setting. This review examines its therapeutic potential in this evolving landscape. A systematic literature search using PubMed and ClinicalTrials.gov identified 153 clinical trials published between 2017 and November 2024, from which ten studies met our strict inclusion criteria, focusing solely on fulvestrant monotherapy. These trials encompassed 1038 patients who had prior exposure to CDK4/6 inhibitors. The selected studies were categorized into three groups: monotherapy trials (EMERALD, SERENA-2, AMEERA-3, and ELAINE-1), combination therapy trials (CAPItello-291 and VERONICA), and CDK4/6 inhibitor rechallenge trials (post-MONARCH, PACE, PALMIRA, and MAINTAIN). The median progression-free survival for fulvestrant monotherapy was 3.18 months (range 1.9–5.3 months). Factors affecting the efficacy of fulvestrant monotherapy in second-line therapy include prior treatments, treatment duration, and genetic mutations. Given that the efficacy of fulvestrant was short-lived in the second or subsequent lines, participating in clinical trials is a vital option until a novel alternative treatment choice becomes available. Full article
(This article belongs to the Section Clinical Research of Cancer)
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20 pages, 812 KiB  
Review
Advances in CDK4 and 6 Inhibitors: Transforming Breast Cancer Treatment
by Sonia Santander Ballestín, María Abadía Labena, Ana Avedillo-Salas, Cristina Marco Continente, Marina Arribas Blázquez and María José Luesma Bartolomé
Cancers 2025, 17(5), 760; https://doi.org/10.3390/cancers17050760 - 24 Feb 2025
Viewed by 1336
Abstract
Background and Objectives: Breast cancer is the most common malignant neoplasm worldwide and the most prevalent one among women. It represents the leading cause of cancer-related death among females. Cyclin-dependent kinase 4 and 6 inhibitors disrupt the cell cycle, inducing cellular senescence and, [...] Read more.
Background and Objectives: Breast cancer is the most common malignant neoplasm worldwide and the most prevalent one among women. It represents the leading cause of cancer-related death among females. Cyclin-dependent kinase 4 and 6 inhibitors disrupt the cell cycle, inducing cellular senescence and, ultimately, apoptosis. Consequently, they have become a novel type of adjuvant therapy for the treatment of advanced or metastatic breast cancer characterised by positive hormone receptors and human epidermal growth factor receptor 2 (HER-2) negative. Methods: A systematic review was conducted, analysing the available literature on cyclin-dependent kinase 4 and 6 inhibitors published over the last five years. The aim was to evaluate the efficacy and safety of adding these drugs to the standard endocrine therapy for this pathology. Results: The combination of cyclin-dependent kinase 4 and 6 inhibitors with endocrine therapy was shown to improve progression-free survival, overall survival, and chemotherapy-free intervals in patients who received this combination therapy. Conclusions: The addition of CDK4/6 inhibitors to endocrine therapy in the treatment of advanced or metastatic breast cancer with positive hormone receptors and HER-2 negative significantly improved PFS, median survival, and chemotherapy-free intervals compared with the use of hormonal treatments alone or in combination with a placebo. Currently, CDK4/6 inhibitors are becoming established as a new standard treatment for this pathology, offering lower toxicity than chemotherapy. However, it is necessary to deeply investigate the mechanisms of treatment resistance and develop effective therapies to overcome them. Full article
(This article belongs to the Special Issue New Perspectives in the Management of Breast Cancer)
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21 pages, 5898 KiB  
Article
Binding Mechanism of Inhibitors to CDK6 Deciphered by Multiple Independent Molecular Dynamics Simulations and Free Energy Predictions
by Lifei Wang, Yan Wang, Lulu Zhang, Juan Zhao, Shiliang Wu and Zhiyong Yang
Molecules 2025, 30(5), 979; https://doi.org/10.3390/molecules30050979 - 20 Feb 2025
Viewed by 750
Abstract
Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations of four separate replicates and computations of binding free energies are carried out to decipher the binding [...] Read more.
Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations of four separate replicates and computations of binding free energies are carried out to decipher the binding mechanisms of three inhibitors, LQQ, 6ZV, and 0RS, to CDK6. The dynamic analyses indicate that the presence of inhibitors influences conformational alterations, motion modes, and the internal dynamics of CDK6. Binding free energies computed using the molecular mechanics generalized Born surface area (MM-GBSA) approach with four GB models demonstrate that hydrophobic interactions play essential roles in inhibitor–CDK6 binding. The computations of residue-based free energy decomposition verify that the side chains of residues I19, K29, M54, P55, F98, H100, and L152 significantly contribute to inhibitor–CDK6 binding, revealing the critical interaction sites of inhibitors for CDK6. The information revealed in our current study can provide theoretical aids for development of potent inhibitors targeting the CDK family. Full article
(This article belongs to the Special Issue Pharmaceutical Modelling in Physical Chemistry)
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18 pages, 1134 KiB  
Article
Evaluating the Effectiveness of Cyclin-Dependent Kinase 4/6 Inhibitors in Early- and Very Early-Onset Metastatic Breast Cancer: A Multicenter Study
by Akif Doğan, Nurullah İlhan, Goncagül Akdağ, Sedat Yıldırım, Mustafa Seyyar, Zeynep Yüksel Yaşar, Hande Nur Erölmez, Heves Sürmeli, Buğra Öztosun, Özlem Nuray Sever, Hatice Odabaş, Mahmut Emre Yıldırım, Devrim Çabuk, Nedim Turan and Mahmut Gümüş
Medicina 2025, 61(1), 154; https://doi.org/10.3390/medicina61010154 - 17 Jan 2025
Viewed by 1320
Abstract
Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined [...] Read more.
Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches. Full article
(This article belongs to the Section Oncology)
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11 pages, 19493 KiB  
Article
Transcriptomic Changes in Human Tonsil-Derived Mesenchymal Stem Cells Across Culture Passages
by Moon Sik Oh, Heesun Hong, Ok Joo Lee, Su Hyeon Yi, Hae Sang Park, Jae-Jun Lee, Chan Hum Park and Sun-Wha Im
Genes 2024, 15(12), 1626; https://doi.org/10.3390/genes15121626 - 19 Dec 2024
Cited by 1 | Viewed by 763
Abstract
Background/Objectives: Tonsil-derived mesenchymal stem cells (TMSCs) are in the limelight in regenerative medicine due to their high proliferation and differentiation potential. It is important to conduct studies to determine the optimal conditions for achieving the maximum yield while maintaining the optimal differentiation capacity [...] Read more.
Background/Objectives: Tonsil-derived mesenchymal stem cells (TMSCs) are in the limelight in regenerative medicine due to their high proliferation and differentiation potential. It is important to conduct studies to determine the optimal conditions for achieving the maximum yield while maintaining the optimal differentiation capacity of TMSCs. Methods: This study explores the impact of serial subculture on TMSCs by analyzing gene expression at passages 2, 4, 6, and 8. For each culture passage, genes with significant differences in RNA expression from previous passages were selected and their characteristics were observed performing enrichment analysis including KEGG (Kyoto Encyclopedia of Genes and Genomes) and Reactome pathway. Results: At each passage, a “cell cycle” term was ranked high with statistical significance in the KEGG and Reactome pathway. Cell cycle gene expression, including Cyclin-dependent kinases (CDKs) and cyclins, increased until passage 6, then decreased by passage 8. The cell cycle is known to be important not only for proliferation but also for determining whether stem cells maintain pluripotency or differentiate into various lineages. Conclusions: The results suggest that cell cycle gene expression can guide the timing for differentiation induction, with passage 6 potentially being a critical point for initiating differentiation. Full article
(This article belongs to the Section Technologies and Resources for Genetics)
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