Search Results (874)

The taxane family of compounds, including paclitaxel, docetaxel (Taxotere), and cabazitaxel (Jevtana), are common drugs used in chemotherapy for the frontline treatment of most major types of cancer. Alopecia, the dramatic loss of hair, is a common side effect that became a symbol of the suffering of many cancer patients. Concerted efforts have been made to understand the mechanism of taxane toxicity to hair follicles and, thus, prevention methods. Taxanes act by stabilizing cellular microtubules, which consequently cause mitotic arrest and then failure, as microtubules play critical functions in chromosome segregation. Hair follicle matrix cells are highly proliferative and thus are exceedingly sensitive to taxanes. We review the cellular mechanism-based strategies under investigation to counter taxane-induced hair follicle damage. These include the application of cyclin kinase inhibitors to block mitotic entry, the practical method using scalp cooling to reduce exposure of scalp hair follicles to drugs during infusion, the requirement of p53 action for hair follicle damage, and the recently discovered method of using low-intensity ultrasound to break taxane-stabilized microtubules and thus reverse taxane toxicity in hair follicle matrix cells. The concept of low-intensity ultrasound as an antidote to taxanes may have the potential to provide a practical and compelling strategy to counter alopecia in cancer treatment using taxanes. Tweet: Taxanes (paclitaxel/docetaxel) are powerful microtubule-stabilizing cancer drugs, but they also cause adverse effects, including alopecia. New research discoveries of temporary microtubule disruption by low-intensity ultrasound may counteract taxane toxicity and prevent alopecia during cancer chemotherapy. “Mechanistic-based strategies for the prevention of taxane-induced hair follicle damage in cancer chemotherapy” OUTLINE: 1. Taxane/paclitaxel mechanism of action in cancer therapy. 2. Taxane side effects: Alopecia (hair loss). 3. p53 dependence of taxane-induced hair follicle damage. 4. Research efforts to counter taxane -induced alopecia by CDK4/6i. 5. Prevention of taxane chemotherapy side effects using scalp cooling. 6. Discovery of low-intensity ultrasound as an antidote for taxane cytotoxicity, and potential prevention of alopecia in chemotherapy using taxanes. 7. Summary and prospective. Full article

CDK4/6 inhibitors such as palbociclib, ribociclib and abemaciclib are commonly used in the clinical treatment of HR-positive, HER2-negative metastatic or locally advanced breast cancer. Patients with metastatic disease often receive palliative radiotherapy for symptom control of bone metastases and/or local lesions, typically administered in close temporal proximity to CDK4/6 inhibitor therapy, although treatment with the inhibitors may be temporarily paused during the radiotherapy period in some cases. In this study, we investigated the extent to which senescence is induced by CDK4/6 inhibitors, ionizing radiation, and the combination of the two, compared to other types of cell fate. Eight breast cancer cell lines with different molecular subtypes and two healthy cell lines (fibroblasts and keratinocytes) were treated with CDK inhibition using palbociclib, ribociclib or abemaciclib and with or without a single dose of 2 Gy ionizing radiation. Cellular senescence, cell death in form of apoptosis and necrosis, and the cell cycle were analyzed using flow cytometry. We focused mainly on understanding how CDK inhibition can trigger cellular senescence. Our data showed that in many cell lines —but not all—the use of CDK inhibitors induced senescence much more strongly than cell death. Except for one cell line, significantly more cell lines died necrotically than apoptotically. Neither apoptosis nor necrosis was responsible for a major cell fate after CDK inhibition. Combination therapy with irradiation did not show a clear additive effect. In cell lines, senescence is clearly triggered by CDK4/6 inhibitors and even more so when in combination with ionizing radiation, which, when transferred to patients, could lead to less damage caused by cell loss, such as necrotic areas. However, it could also lead to more senescence-specific side effects, such as inflammation-induced tumors and fibrosis. Full article

Natural killer (NK) cells are effector cells of the innate immune system. The cytokine microenvironment influences NK cell function. Dysregulation of NK cell cytotoxicity can manifest in reproductive disorders and is also observed in tumor-transformed tissues. The search for immunotherapies capable of regulating NK cell activity is therefore relevant. This study aimed to evaluate the effect of the TGFβ signaling pathway inhibitor and the cyclin-dependent kinase (CDK) 7/12/13 inhibitor on the transcriptional profile of NK-92 cell line. In the study, the cytokines TGFβ1, IL-12, IL-15, IL-18, and TNFα, and the TGFβ receptor type 1 (TGFβR1) inhibitor LY3200882 and the CDK7/12/13 inhibitor THZ1 were used. The cells were cultured sequentially in the presence of inhibitors and cytokines, followed by assessment of the gene expression of NCR2, NCR3, AHR, NCAM1, B3GAT1, EOMES, GATA3, KLRC1, KLRC2, CCL5, IL10 and TBX21. We observed direct effects of the inhibitors on NK cells. LY3200882 increased the expression of KLRC1 and B3GAT1, and reduced NCAM1. THZ1 increased the expression of KLRC1, KLRC2, AHR and EOMES, while it reduced IL-10 and NCR2. IL-12, IL-15, IL-18, and TNFα modified the gene expression of some phenotypic and cytotoxic receptors and transcription factors. TGFβ1 increased the expression of KLRC1, NCAM1, and B3GAT1. Blocking TGFβ-dependent signaling with LY3200882 abolished TGFβ1 effects. We assessed CD56 presence on NK-92 cell membrane and found its increase in the presence of LY3200882. After LY3200882 treatment, in the presence of TGFβ1 and choriocarcinoma cell line JEG-3, the expression of CD56 receptor on NK cell membrane decreased. Pretreating NK cells with THZ1 decreased the expression of NCAM1, B3GAT1, and EOMES in the presence of TGFβ1. Thus, LY3200882 partially neutralized TGFβ1 effects on the expression of NK cell receptor genes. THZ1 followed by TGFβ1 treatment promoted NK cell transcriptional profile characteristic for CD56dim NK cells. Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered. Full article

Background: Hormone receptor-positive (HR+), Human Epidermal growth factor Receptor 2 (HER2-negative) metastatic breast cancer (MBC) represents a substantial proportion of breast cancer cases in Saudi Arabia. Despite the established efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, particularly Palbociclib, in randomized control trials, real-world data from local institutions in Saudi Arabia remain limited. Objectives: This study aimed to evaluate progression-free survival (PFS), overall survival (OS), and toxicity profile among HR+, HER2-negative MBC female patients treated with Palbociclib at King Fahad Medical City (KFMC). Methods: A retrospective study was conducted on female patients with HR+/HER2-negative MBC treated with oral palbociclib combined with endocrine therapy (ET) at KFMC between January 2021 and September 2024. Data were collected from electronic health records. Descriptive statistics were conducted using mean for continuous variables and frequency for categorical variables. Survival analyses were conducted using Cox regression, log-rank tests and Kaplan–Meier analysis. Results: A total of 169 female patients with HR+/HER2− MBC were included. In the first-line setting, the median PFS was 20.14 months (95% CI: 14.65–30.49), compared with 11.3 months (95% CI: 7.98–not estimable) in the second-line setting. For OS, the median OS values were 53.1 months (95% CI: 41.2–not estimable) in the first-line group and 23.7 months (95% CI: 18.5–not estimable) in the second-line group. Significant predictors of shorter PFS included age, Body Mass Index (BMI), type of ET, cancer type, line of therapy, family history of cancer, and history of VTE. Visceral metastasis (HR = 3.087; p = 0.0229) and ECOG performance status of 4 (HR = 13.86; p = 0.0156) were associated with significantly shorter OS. The most common hematological adverse events (AEs) were neutropenia (45.6%), followed by anemia (5.9%), leukopenia (5.3%), and back pain (5.3%). Most toxicities were managed with dose reduction, holding treatment, or supportive care. Conclusions: Palbociclib demonstrated favorable survival outcomes and a manageable safety profile, with neutropenia being the most common AE. This study provides region-specific real-world evidence supporting the use of Palbociclib in HR+/HER2− MBC. These findings align with global trial data and highlight the importance of individualized treatment in clinical practice. Full article

The treatment paradigm for HER2-positive metastatic breast cancer has evolved from continuous chemotherapy-based regimens to a model of finite chemotherapy induction followed by sustained antibody-driven disease control. The CLEOPATRA trial established dual HER2 blockade with trastuzumab and pertuzumab plus a taxane as the biological and clinical anchor of this approach, demonstrating that chemotherapy is administered for a defined induction period, after which antibody maintains disease suppression. An increasing body of clinical evidence indicates that antibody-based regimens can be combined with targeted agents, including CDK4/6 inhibitors or HER2 tyrosine kinase inhibitors, to achieve durable disease control without the need for continuous chemotherapy. In the PATINA trial, the addition of palbociclib to trastuzumab, pertuzumab, and endocrine therapy was associated with a clinically meaningful improvement in progression-free survival in hormone receptor-positive, HER2-positive metastatic breast cancer. At the same time, quality of life was maintained despite higher rates of hematologic toxicity. More recently, HER2-CLIMB-05 demonstrated that the addition of tucatinib to dual HER2 antibody therapy significantly prolonged progression-free survival, supporting a model of sustained, multi-agent HER2 pathway suppression. The monarcHER trial provided biological proof of concept that antibody plus CDK4/6 inhibition can achieve disease control without chemotherapy in hormone receptor-positive, HER2-positive disease. Collectively, these advances support a translational framework in which antibody therapy serves as a central component of treatment strategies, with targeted partners selected according to tumor biology and prior therapy. This review summarizes the biological basis, clinical evidence, and future perspectives of antibody-driven maintenance in HER2-positive metastatic breast cancer. Full article

Background/Objectives: Protein kinases play a crucial role in cancer initiation, progression, and therapeutic resistance by regulating signalling pathways involved in tumour growth and survival. Consequently, they represent major targets in anticancer drug discovery. Among heterocyclic scaffolds explored in kinase inhibitor design, benzimidazole has emerged as a privileged structure due to its strong hydrogen-bonding capability and structural resemblance to purine moieties. Triazole motifs are also widely incorporated into bioactive molecules because of their metabolic stability, favourable electronic properties, and ability to establish key interactions within kinase active sites. This review aims to summarise and critically discuss benzimidazole- and triazole-based kinase inhibitors, both as individual scaffolds and as hybrid systems, with emphasis on their kinase targets and multitarget potential. Methods: The relevant literature was surveyed from major scientific databases focusing on studies describing the synthesis, biological evaluation, and molecular modelling of benzimidazole- and triazole-containing kinase inhibitors. Results: Numerous studies demonstrate that both benzimidazole and triazole scaffolds exhibit significant kinase inhibitory activity against oncogenic targets, including EGFR, cyclin-dependent kinases (CDKs), and components of the PI3K/Akt/mTOR signalling pathway. Hybrid molecules combining these pharmacophores frequently enhance binding interactions and facilitate the development of multitarget kinase inhibitors. Structure–activity relationship trends indicate that pharmacophore accessibility, substitution patterns, and linker architecture influence inhibitory potency and selectivity. Conclusions: Overall, benzimidazole- and triazole-based scaffolds represent promising platforms for developing next-generation multitarget anticancer agents and provide valuable insights for the rational design of improved kinase inhibitors. Full article

Background: Hormone receptor-positive/HER2-negative (HR+/HER2−) early breast cancer (EBC) presents a persistent risk of relapse, even beyond 5 years, driving the need for adjuvant intensification strategies. This review analyzes the clinical evidence for CDK4/6 inhibitors (CDK4/6i) in the adjuvant setting. This evidence is then integrated with molecular findings to support the concept of the “carry-over” effect, which is understood as a lasting benefit that persists after the end of active treatment, reflected by a sustained separation of invasive disease-free survival (iDFS) curves during follow-up. Relevant Sections: The main adjuvant trials in EBC are reviewed, with consideration of the “carry-over” effect. Emerging biomarkers and the impact of financial toxicity are also described. Results: PALLAS did not demonstrate a clear on-treatment or post-treatment benefit, whereas PENELOPE-B suggested, at most, a transient early advantage that was not maintained with longer follow-up; therefore, neither trial provides convincing evidence of a durable “carry-over” effect. In contrast, monarchE (abemaciclib) and NATALEE (ribociclib) showed significant improvements in iDFS and, in the case of abemaciclib, a signal of benefit in overall survival, supporting the existence of a clinically relevant post-treatment effect. Conclusions: From a biological perspective, the review proposes that the “carry-over” effect should not be considered a uniform class effect, but rather the result of a sequence of events modulated by pharmacological selectivity (CDK4 vs. CDK6 and additional targets), the induction of cellular senescence, and immunomodulatory effects that could favor the control of micrometastases. In addition, elements that influence interpretation and the need to optimize adherence and toxicity management to “materialize” the benefit in a potentially curable context are discussed. Full article

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy, has significantly improved clinical outcomes and has become a standard treatment strategy in both metastatic and high-risk early-stage disease. Nevertheless, treatment resistance and disease progression remain major clinical challenges. A deeper understanding of the structural characteristics of CDK4/6 and the molecular basis of inhibitor binding is therefore essential for improving therapeutic strategies and guiding the development of new targeted agents. This review provides an integrated overview of the structural features of CDK4/6 and their role in cell cycle regulation, summarizes the clinical development and major clinical trials of currently approved CDK4/6 inhibitors, and discusses recent computational studies investigating inhibitor binding and conformational dynamics. Particular attention is given to the application of in silico approaches, including molecular docking, molecular dynamics simulations, and binding free-energy calculations, which provide insights into mechanisms of therapy resistance and potential strategies to overcome them and support the identification and optimization of novel CDK4/6-targeted therapeutic candidates. By integrating structural, clinical, and computational perspectives, this review highlights current knowledge and emerging directions in CDK4/6 research that may advance the development of more personalized therapies for HR+/HER2− breast cancer, while accounting for both intrinsic and de novo resistance mechanisms. Full article

Background: Oral progestogens, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA), have largely been superseded by aromatase inhibitors, tamoxifen, and selective oestrogen receptor degraders (SERDs) in oestrogen receptor-positive (ER-positive) metastatic breast cancer. However, they remain an option as late-line therapy after failure of standard treatments. Contemporary data are limited, particularly in patients previously treated with CDK4/6 inhibitors. Methods: We conducted a multi-site retrospective analysis of patients with ER-positive metastatic breast cancer treated with MA or MPA between 2014 and 2024 at four hospital sites across London, United Kingdom. Patients were identified using pharmacy dispensing records. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and Cox regression. Subgroup analyses included prior CDK4/6 inhibitor exposure, histology and liver metastases. Results: A total of 116 patients were included. Median PFS was 2.4 months (95% CI 2.2–2.9), and median OS was 3.3 months (95% CI 2.7–4.9). Prior CDK4/6 inhibitor exposure was associated with shorter PFS (1.9 vs. 2.8 months; HR 1.59; 95% CI 1.08–2.35, p = 0.019) and a trend toward shorter OS (3.1 vs. 3.6 months; HR 1.18, 95% CI 0.80–1.75, p = 0.41). Similarly, liver metastases were associated with shorter PFS (2.3 vs. 2.8 months; HR 1.78, 95% CI 1.12–2.85, p = 0.015), with a trend toward worse OS (3.1 vs. 4.9 months; HR 1.45, 95% CI 0.93–2.25, p = 0.103). A subset of patients derived prolonged benefit, with a 6-month PFS rate of 16%. Toxicity was manageable; thromboembolic events and oedema occurred in 9% and 11% of patients respectively. Appetite improvement was reported in 10%. Conclusions: MA and MPA demonstrated modest but clinically relevant late-line activity in heavily pretreated, endocrine-refractory ER-positive metastatic breast cancer. While prior exposure to CDK4/6 inhibitors was associated with shorter PFS, patients without liver metastases appeared to derive the greatest benefit. These findings support a role for oral progestogens in selected patients who have exhausted standard therapeutic options. Full article

The retinoblastoma (RB) protein was the first tumor suppressor discovered and has been extensively studied for its canonical role in cell-cycle regulation. However, RB has broader noncanonical roles in DNA damage repair, chromosomal stability, apoptosis control, lineage commitment, cell differentiation and broad transcriptional regulation. Historically, RB inactivation has been associated with tumorigenesis, as well as resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), leading to its investigation as a potential predictive biomarker. However, clinical data have not demonstrated that RB function reliably predicts response to CDK4/6i consistently. These discrepancies highlight the need to reconsider RB’s role in therapeutic response, as RB loss can promote replication stress, induce chromosomal instability, and lead to transcriptional reprograming, potentially generating context-specific therapeutic vulnerabilities. In this review, we examine the multifaceted biology of RB and evaluate how its loss influences responses to chemotherapy and targeted therapies. We highlight emerging strategies that exploit RB-deficient states using rational monotherapy and combination approaches. Reframing RB dysfunction from a binary biomarker to a driver of exploitable cellular vulnerabilities may inform and expand precision oncology strategies for aggressive and treatment-resistant cancers. Full article

Breast cancer is the second most common malignancy worldwide, and over 70% of new diagnosis are of the hormone receptor-positive (HR+) and HER2-negative (HER2−) subtype. The cornerstone in management of early stage HR+ breast cancer has historically consisted of chemotherapy and endocrine therapies. Genomic assays in early stage HR+HER2− breast cancer has provided a prognostic tool for recurrence and a predictive tool to select patients for adjuvant chemotherapy. The introduction of bone-modifying agents and adjuvant CDK 4/6 inhibitors into early stage disease represents new therapeutic modalities aimed at reducing risk in high-risk HR+HER2− cancers. This manuscript aims to provide a comprehensive overview of the evidence behind endocrine therapy and recommended duration of treatment, genomic assays to guide chemotherapy delivery, data guiding use of bisphosphonate therapy to reduce bone recurrence, and indications for incorporating CDK 4/6 inhibitors. In addition, novel endocrine agents and targeted therapies under investigation are highlighted. Full article

Background and Objectives: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are recommended as first- or second-line treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or recurrent breast cancer. However, in clinical practice, initiation timing varies according to patient characteristics, prior treatments, and the choice of the physician. Thus, the optimal timing of combination treatment remains unclear. Materials and Methods: In this multicenter retrospective cohort study, we reviewed 66 female patients who received CDK4/6i (palbociclib or abemaciclib) between March 2018 and November 2019. Patients were categorized into the first-line treatment (group A) (n = 21) and second- or subsequent-line treatment (group B) (n = 45) groups. In the latter group, endocrine therapy and/or chemotherapy had been administered previously. Duration of treatment with CDK4/6i (DOT), overall survival (OS), treatment duration of other regimens, and reasons for treatment discontinuation after CDK4/6i treatment were compared between groups. Results: The median DOT was significantly longer in group A than in group B (23 months (95% CI, 8–43) vs. 7 months (95% CI, 3–15); p = 0.015, at log-rank test). OS showed no significant difference between the two groups (p = 0.69, at log-rank test). Conclusions: In patients with HR-positive, HER2-negative advanced or recurrent breast cancer, first-line use of CDK4/6 inhibitors was associated with a significantly longer duration of treatment compared with second- or subsequent-line use. However, no significant difference in OS was observed between patients receiving CDK4/6 inhibitors as first-line or second- or subsequent-line therapy. Full article

Background: This study aims to evaluate the real-world efficacy and safety of dalpiciclib in patients with hormone receptor-positive (HR+) advanced breast cancer and explore the impact of different clinical characteristics on treatment outcomes. Methods: This was a two-center, retrospective cohort study involving 76 patients treated with dalpiciclib between January 2022 and June 2024 at two affiliated hospitals of Anhui Medical University in China. Data on progression-free survival (PFS), adverse events, and key clinical factors were collected and analyzed. Kaplan–Meier estimates were used for statistical analysis. Results: The median PFS (mPFS) for the entire cohort was 12.00 months (95% CI: 10.09–13.91 months). Patients receiving dalpiciclib as first-line therapy had significantly better outcomes (mPFS: 17.00 months, 95% CI: 9.19–24.81 months) than those receiving later-line therapy (p < 0.001). Patients with prior exposure to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and those with endocrine resistance had poorer outcomes. Multivariate Cox proportional hazards regression analysis confirmed that earlier treatment line (HR for second-line vs. first-line: 3.89, p = 0.015; HR for third-line or later vs. first-line: 5.56, p = 0.006) and prior CDK4/6i treatment (HR = 3.42, p = 0.040) were independent predictors of PFS. The most common adverse events were hematologic toxicities, including leukopenia (76.6%) and neutropenia (72.4%), mostly grade 1–2. No febrile neutropenia cases were reported, indicating a manageable safety profile. Conclusions: Dalpiciclib combined with endocrine therapy is associated with favorable efficacy and safety in real-world settings, with early-line treatment and lower tumor proliferative activity associated with better outcomes. While findings suggest potential for clinical application, further large-scale prospective studies are needed to validate its effectiveness in different patient subgroups and optimize treatment strategies. Full article

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies of tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic, and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the “transcriptional addiction” that not only drives cancer cell growth but is also attributed to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches, including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt tCDK functions in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions. Full article

Dengue virus (DENV) is a mosquito-borne RNA virus that causes serious illness in humans, ranging from mild fever to severe clinical manifestations, with dengue virus type 2 (DENV-2) being the most virulent among its four serotypes. Despite extensive research, no specific antiviral therapy is currently available, making the host-directed method an appealing therapeutic approach. Evidence shows that DENV manipulates host kinase-driven phosphorylation pathways to control viral pathogenesis. Using the kinase–substrate phosphomotif approach, we predicted phosphorylation sites across the DENV proteome and their potential human kinases. The predicted kinase–substrate interactions were systematically integrated with DENV-2-induced human phosphoproteome datasets, protein–protein interactions, and experimentally-validated viral phosphosites. The therapeutic relevance of the identified host kinases was corroborated by the impact of their inhibitors on DENV-2 infection. Among the 359 potential human kinases predicted to phosphorylate DENV-2 proteins, based on human phosphoproteome and kinase–viral protein interaction analyses, CDK9 emerged as a central hub kinase. Molecular docking analyses further revealed that the host kinases CDK9, EEF2K, HASPIN, and TNNI3K form stable interactions with the viral capsid and NS5 proteins. Additionally, a conservation analysis suggested that the predicted phosphorylation sites are evolutionarily conserved across DENV-2 strains. Computational prediction tools supported the predicted kinase–substrate interactions, underscoring the role of host kinases as key regulators of DENV infection, which may act as potential therapeutic targets. This study highlights the interplay between dengue viral and host proteins, providing insights into host-directed therapeutic strategies for DENV-2 infection and their potential to address the current lack of effective antiviral interventions. Full article