Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

Mast cells: Therapeutic targets for COVID-19 and beyond.

Mast cells (MCs) are innate immune cells that widely distribute throughout all tissues and express a variety of cell surface receptors. Upon activation, MCs can rapidly release a diverse array of preformed mediators residing within their secretory granules and newly synthesize a broad spectrum of inflammatory and immunomodulatory mediators. These unique features of MCs enable them to act as sentinels in response to rapid changes within their microenvironment. There is increasing evidence now that MCs play prominent roles in other pathophysiological processes besides allergic inflammation. In this review, we highlight the recent findings on the emerging roles of MCs in the pathogenesis of coronavirus disease-2019 (COVID-19) and discuss the potential of MCs as novel therapeutic targets for COVID-19 and other non-allergic inflammatory diseases.

Glutathione attenuates nitric oxide-induced retinal lipid and protein changes.

BACKGROUND: Elevated levels of nitric oxide (NO(•) ), a pro-oxidant that has been associated with numerous retinal diseases, have been implicated in experimental glaucoma models. This study investigated the oxidative effects of sodium nitroprusside (SNP), a nitric oxide donor, on the retinal lipids and proteins and evaluated the potential protective effects of glutathione (GSH). METHODS: Porcine retinal homogenates were incubated with 0, 1, 2, 3, 4 and 5 µm SNP. Malondialdehyde (MDA) levels were assayed spectrophotometrically to quantify lipid peroxidation. Differential protein expressions of 3 µm SNP-treated retinal homogenates were compared with controls after the conduction of two-dimensional gel electrophoresis. Mass spectrometric data was used to identify proteins in NCBInr database. Furthermore, GSH was co-incubated with 3 µm SNP-treated retinal homogenates. MDA levels and protein expressions were compared with SNP-treated controls. RESULTS: SNP significantly increased retinal-MDA levels (p = 0.0002). 2-D gel electrophoresis images displayed a significant change in 13 protein spot expressions (p < 0.05). GSH suppressed SNP-induced MDA elevation (p < 0.0001) and selected protein changes (p < 0.05). SNP down-regulated paraoxonase/arylesterase 2 precursor (PON2), ß-actin and ß-tubulin; however, these effects were prevented by a co-incubation with GSH, as confirmed by Western blots. CONCLUSIONS: Nitric oxide induced lipid and protein changes in retinal tissues. The effects were partially reversed by co-incubation with GSH. Data from this study suggests that nitric oxide-induced retinal oxidative stress induces specific molecular changes. This may enable us to better understand the pathogenesis of glaucoma. Further studies are indicated to explore potential pharmacological applications of GSH in nitric oxide-related retinal diseases.

Delineating the role of nuclear receptors in colorectal cancer, a focused review.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

SHP2 inhibitors maintain TGFß signalling through SMURF2 inhibition.

Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits TGFß activity by ubiquitinating and targeting the TGFß receptor for proteosome degradation. Using a functional RNAi screen targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFß activity. Specifically, SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains SMURF2 in an inactive state, resulting in the maintenance of TGFß activity. Furthermore, we demonstrate that depleting SHP2 has significant implications on TGFß-mediated migration, senescence, and cell survival. These effects can be overcome through the use of TGFß-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFß inhibitors to enhance tumour responses leading to improved patient outcomes.

Mechanisms of allergen-specific immunotherapy for allergic rhinitis and food allergies.

Allergen-specific immunotherapy (AIT) is currently the only potential treatment for allergies including allergic rhinitis (AR) and food allergies (FA) that can modify the underlying course of the diseases. Although AIT has been performed for over a century, the precise and detailed mechanism for AIT is still unclear. Previous clinical trials have reported that successful AIT induces the reinstatement of tolerance against the specific allergen. In this review, we aim to provide an updated summary of the knowledge on the underlying mechanisms of IgE-mediated AR and FA as well as the immunological changes observed after AIT and discuss on how better understanding of these can lead to possible identification of biomarkers and novel strategies for AIT.

ELKS1 controls mast cell degranulation by regulating the transcription of Stxbp2 and Syntaxin 4 via Kdm2b stabilization.

ELKS1 is a protein with proposed roles in regulated exocytosis in neurons and nuclear factor κB (NF-κB) signaling in cancer cells. However, how these two potential roles come together under physiological settings remain unknown. Since both regulated exocytosis and NF-κB signaling are determinants of mast cell (MC) functions, we generated mice lacking ELKS1 in connective tissue MCs (Elks1f/f Mcpt5-Cre) and found that while ELKS1 is dispensable for NF-κB-mediated cytokine production, it is essential for MC degranulation both in vivo and in vitro. Impaired degranulation was caused by reduced transcription of Syntaxin 4 (STX4) and Syntaxin binding protein 2 (Stxpb2), resulting from a lack of ELKS1-mediated stabilization of lysine-specific demethylase 2B (Kdm2b), which is an essential regulator of STX4 and Stxbp2 transcription. These results suggest a transcriptional role for active-zone proteins like ELKS1 and suggest that they may regulate exocytosis through a novel mechanism involving transcription of key exocytosis proteins.