Cyclin-dependent kinases (CDKs) are overexpressed in tumor cells, and their aberrant activation can promote the progression of non-small-cell lung cancer (NSCLC). We utilized structure-based virtual screening and experimental validation to screen for potential CDKs antagonists among TargetMol natural products. Molecular docking and molecular dynamics simulation results indicate that Dolastatin 10 exhibits strong interactions with multiple subtypes of CDKs (CDK1, CDK2, CDK3, CDK4, and CDK6), forming stable CDKs-Dolastatin 10 complex compounds. Furthermore, in vitro experiments demonstrate that Dolastatin 10 significantly inhibits the viability, migration, and invasion of H1299 cells in a concentration-dependent manner, arresting the cell cycle at the G2/M phase by inducing cell senescence. These findings suggest that Dolastatin 10 may serve as a potential CDKs antagonist deserving further investigation.

BACKGROUND: Exploring the value of baseline and early 18F-FDG PET/CT evaluations in prediction PFS in ER+/HER2- metastatic breast cancer patients treated with a cyclin-dependent kinase inhibitor in combination with an endocrine therapy.
METHODS: Sixty-six consecutive breast cancer patients who underwent a pre-therapeutic 18F-FDG PET/CT and a second PET/CT within the first 6 months of treatment were retrospectively included. Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and Dmax, which represents tumour dissemination and is defined as the distance between the two most distant lesions, were computed. The variation in these parameters between baseline and early evaluation PET as well as therapeutic evaluation using PERCIST were assessed as prognosticators of PFS at 18 months.
RESULTS: The median follow-up was equal to 22.5 months. Thirty progressions occurred (45.4%). The average time to event was 17.8 ± 10.4 months. At baseline, Dmax was the only predictive metabolic parameter. Patients with a baseline Dmax ≤ 18.10 cm had a significantly better 18 m-PFS survival than the others: 69.2% (7.7%) versus 36.7% (8.8%), p = 0.017. There was no association between PERCIST evaluation and 18 m-PFS status (p = 0.149) and there was no difference in 18 m-PFS status between patients classified as complete, partial metabolic responders or having stable metabolic disease.
CONCLUSIONS: Disease spread at baseline PET, as assessed by Dmax, is predictive of an event occurring within 18 months. In the absence of early metabolic progression, which occurs in 15% of patients, treatment should be continued regardless of the quality of the initial response to treatment.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome caused by inactivating pathogenic variants in the tumor suppressor gene menin 1 on chromosome 11q13 (Falchetti et al., 2009). The syndrome is characterized by neoplasia in two or more endocrine glands and has a high degree of penetrance. Pathogenic germline multiple neoplasia type 1 variants primarily result in neoplasia affecting the parathyroid glands, the pancreatic islet cells, and the anterior pituitary in combination. Primary hyperparathyroidism is the most common pathological manifestation of the syndrome, followed by pancreatic neuroendocrine tumors. Important genetic confirmation has been provided showing that ependymoma should be considered as a neoplasm that can occur in patients with MEN1 (Kato et al., 1996; Cuevas-Ocampo et al., 2017). The biphasic histopathological tumor entity shown in the present case we name Pleomorphic Xanthoastocytoma grade 3 differential pathology (PDP) in association with Multiple Endocrine Neoplasia type 1. This MEN1 associated tumor subtype is an extension of the findings on MEN1 associated ependymoma, where we show that the clinical phenotype itself may potentially be triggered by a frameshift germline pathogenic variant for the MEN1 gene, in combination with cyclin-dependent kinase inhibitor 1B gene germline variant and cyclin dependent kinase inhibitor 2A somatic deletion downstream of menin.

暂无摘要。

The cyclin-dependent kinase 1 (Cdk1)-cyclin B (CycB) complex plays critical roles in cell-cycle regulation. Before Drosophila male meiosis, CycB is exported from the nucleus to the cytoplasm via the nuclear porin 62kD (Nup62) subcomplex of the nuclear pore complex. When this export is inhibited, Cdk1 is not activated, and meiosis does not initiate. We investigated the mechanism that controls the cellular localization and activation of Cdk1. Cdk1-CycB continuously shuttled into and out of the nucleus before meiosis. Overexpression of CycB, but not that of CycB with nuclear localization signal sequences, rescued reduced cytoplasmic CycB and inhibition of meiosis in Nup62-silenced cells. Full-scale Cdk1 activation occurred in the nucleus shortly after its rapid nuclear entry. Cdk1-dependent centrosome separation did not occur in Nup62-silenced cells, whereas Cdk1 interacted with Cdk-activating kinase and Twine/Cdc25C in the nuclei of Nup62-silenced cells, suggesting the involvement of another suppression mechanism. Silencing of roughex rescued Cdk1 inhibition and initiated meiosis. Nuclear export of Cdk1 ensured its escape from inhibition by a cyclin-dependent kinase inhibitor. The complex re-entered the nucleus via importin β at the onset of meiosis. We propose a model regarding the dynamics and activation mechanism of Cdk1-CycB to initiate male meiosis.

Coordination of cell cycle with metabolism exists in all cell types that grow by division. It serves to build a new cell, (i) fueling building blocks for the synthesis of proteins, nucleic acids, and membranes, and (ii) producing energy through glycolysis. Cyclin-dependent kinases (Cdks) play an essential role in this coordination, thereby in the regulation of cell division. Cdks are functional homologs across eukaryotes and are the engines that drive cell cycle events and the clocks that time them. Their function is counteracted by stoichiometric inhibitors; specifically, inhibitors of cyclin-cyclin dependent kinase (cyclin/Cdk) complexes allow for their activity at specific times. Here, we provide a new perspective about the yet unknown cell cycle mechanisms impacting on metabolism. We first investigated the effect of the mitotic cyclin/Cdk1 complex Cyclin B/Cdk1-functional homolog in mammalian cells of the budding yeast Clb2/Cdk1-on yeast metabolic enzymes of, or related to, the glycolysis pathway. Six glycolytic enzymes (Glk1, Hxk2, Pgi1, Fba1, Tdh1, and Pgk1) were subjected to in vitro Cdk-mediated phosphorylation assays. Glucose-6-phosphate dehydrogenase (Zwf1), the first enzyme in the pentose phosphate pathway that is important for NADPH production, and 6-phospho-fructo-2-kinase (Pfk27), which catalyzes fructose-2,6-bisphosphate synthesis, a key regulator of glycolysis, were also included in the study. We found that, among these metabolic enzymes, Fba1 and Pgk1 may be phosphorylated by Cdk1, in addition to the known Cdk1-mediated phosphorylation of Gph1. We then investigated the possible effect of Sic1, stoichiometric inhibitor of mitotic cyclin/Cdk1 complexes in budding yeast, on the activities of three most relevant glycolytic enzymes: Hxk2, Glk1, and Tdh1. We found that Sic1 may have a negative effect on Hxk2. Altogether, we reveal possible new routes, to be further explored, through which cell cycle may regulate cellular metabolism. Because of the functional homology of cyclin/Cdk complexes and their stoichiometric inhibitors across evolution, our findings may be relevant for the regulation of cell division in eukaryotes.

Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) have been shown to improve progression-free survival (PFS) in patients with metastatic breast cancer (MBC) in randomized control trials. This study aimed to evaluate the efficacy and safety of CDK4/6i in patients with advanced breast cancer (ABC) in a clinical setting.
Consecutive patients with ABC were treated between October 2019 and March 2023 at Taipei Tzu Chi Hospital, Taiwan. Patients who had received at least one dose of CDK4/6i were included in this retrospective study. The main outcome of this study was efficacy based on the treating physicians\' assessments in terms of PFS, and overall survival (OS), as well as the factors associated with patient outcome. The secondary outcome was safety.
A total of 85 patients were included in the analysis, with a mean age of 66.8 years. After a median follow-up of 16.1 months, the median PFS was 28.4 months (95% CI: 22.5-33.6) and the median OS could not yet be estimated. The most common adverse events (AE) were fatigue (50.8%), anorexia (45.9%), and leukopenia (44.7%). In multivariable analysis, treatment with CDK4/6i with any grade AE or response to treatment effect (CR/PR) was an independent predictor for longer PFS (hazard ratio [HR] = 0.27, 95% CI: 0.11-0.68; HR = 0.21, 95% CI: 0.06-0.67; p < 0.05).
CDK4/6i administered in a real-world setting exhibits a similar survival benefit with the clinical trials.

BACKGROUND: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors.
METHODS: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity.
RESULTS: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed.
CONCLUSIONS: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development.
BACKGROUND: NCT03770494.

Mast cells (MCs) are immune cells of the myeloid lineage distributed in tissues throughout the body. Phenotypically, they are a heterogeneous group characterized by different protease repertoires stored in secretory granules and differential presence of receptors. To adequately address aspects of MC biology either primary MCs isolated from human or mouse tissue or different human MC lines, like HMC-1.1 and -1.2, or rodent MC lines like L138.8A or RBL-2H3 are frequently used. Nevertheless, cellular systems to study MC functions are very limited. We have generated a murine connective tissue-like MC line, termed PMC-306, derived from primary peritoneal MCs (PMCs), which spontaneously transformed. We analyzed PMC-306 cells regarding MC surface receptor expression, effector functions and respective signaling pathways, and found that the cells reacted very similar to primary wildtype (WT) PMCs. In this regard, stimulation with MAS-related G-protein-coupled receptor member B2 (MRGPRB2) ligands induced respective signaling and effector functions. Furthermore, PMC-306 cells revealed significantly accelerated cell cycle progression, which however was still dependent on interleukine 3 (IL-3) and stem cell factor (SCF). Phenotypically, PMC-306 cells adopted an immature connective tissue-like MCs appearance. The observation of cellular transformation was accompanied by the loss of Cdkn2a and Arf expression, which are both described as critical cell cycle regulators. The loss of Cdkn2a and Arf expression could be mimicked in primary bone marrow-derived mast cells (BMMCs) by sustained SCF supplementation strongly arguing for an involvement of KIT activation in the regulation of Cdkn2a/Arf expression. Hence, this new cell line might be a useful tool to study further aspects of PMC function and to address tumorigenic processes associated with MC leukemia.

BACKGROUND: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses.
METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors.
RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug\'s half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific.
CONCLUSIONS: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.