Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition.

BACKGROUND AND PURPOSE: The PARP inhibitor (PARPi), Talazoparib (BMN673), effectively and specifically radiosensitizes cancer cells. Radiosensitization is mediated by a shift in the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) toward PARP1-independent, alternative end-joining (alt-EJ). DNA polymerase theta (Polθ) is a key component of this PARP1-independent alt-EJ pathway and we show here that its inhibition can further radiosensitize talazoparib-treated cells. The purpose of the present work is to explore mechanisms and dynamics underpinning enhanced talazoparib radiosensitization by Polθ inhibitors in HR-proficient cancer cells. METHODS AND MATERIALS: Radiosensitization to PARPis, talazoparib, olaparib, rucaparib and veliparib was assessed by clonogenic survival. Polθ-proficient and -deficient cells were treated with PARPis and/or with the Polθ inhibitors ART558 or novobiocin. The role of DNA end-resection was studied by down-regulating CtIP and MRE11 expression using siRNAs. DSB repair was assessed by scoring γH2AX foci. The formation of chromosomal abnormalities was assessed as evidence of alt-EJ function using G2-specific cytogenetic analysis. RESULTS: Talazoparib exerted pronounced radiosensitization that varied among the tested cancer cell lines; however, radiosensitization was undetectable in normal cells. Other commonly used PARPis, olaparib, veliparib, or rucaparib were ineffective radiosensitizers under our experimental conditions. Although genetic ablation or pharmacological inhibition of Polθ only mildly radiosensitized cancer cells, talazoparib-treated cells were markedly further radiosensitized. Mechanistically, talazoparib shunted DSBs to Polθ-dependent alt-EJ by enhancing DNA end-resection in a CtIP- and MRE11-dependent manner - an effect detectable at low, but not high IR doses. Chromosomal translocation analysis in talazoparib-treated cells exposed to Polθ inhibitors suggested that PARP1- and Polθ-dependent alt-EJ pathways may complement, but also back up each other. CONCLUSION: We propose that talazoparib promotes low-dose, CtIP/MRE11-dependent resection and increases the reliance of irradiated HR-proficient cancer cells, on Polθ-mediated alt-EJ. The combination of Polθ inhibitors with talazoparib suppresses this option and causes further radiosensitization. The results suggest that Polθ inhibition may be exploited to maximize talazoparib radiosensitization of HR-proficient tumors in the clinic.

A seven-immune-genes risk model predicts the survival and suitable treatments for patients with skin cutaneous melanoma.

Background: Skin cutaneous melanoma is characterized by high malignancy and prognostic heterogeneity. Immune cell networks are critical to the biological progression of melanoma through the tumor microenvironment. Thus, identifying effective biomarkers for skin cutaneous melanoma from the perspective of the tumor microenvironment may offer strategies for precise prognosis prediction and treatment selection. Methods: A total of 470 cases from The Cancer Genome Atlas and 214 from the Gene Expression Omnibus were systematically evaluated to construct an optimal independent immune cell risk model with predictive value using weighted gene co-expression network analysis, Cox regression, and least absolute shrinkage and selection operator assay. The predictive power of the developed model was estimated through receiver operating characteristic curves and Kaplan-Meier analysis. The association of the model with tumor microenvironment status, immune checkpoints, and mutation burden was assessed using multiple algorithms. Additionally, the sensitivity of immune and chemotherapeutics was evaluated using the ImmunophenScore and pRRophetic algorithm. Furthermore, the expression profiles of risk genes were validated using gene expression profiling interactive analysis and Human Protein Atlas resources. Results: The risk model integrated seven immune-related genes: ARNTL, N4BP2L1, PARP11, NUB1, GSDMD, HAPLN3, and IRX3. The model demonstrated considerable predictive ability and was positively associated with clinical and molecular characteristics. It can be utilized as a prognostic factor for skin cutaneous melanoma, where a high-risk score was linked to a poor prognosis and indicated an immunosuppressive microenvironment. Furthermore, the model revealed several potential target checkpoints and predicted the therapeutic benefits of multiple clinically used drugs. Conclusion: Our findings provide a comprehensive landscape of the tumor immune microenvironment in skin cutaneous melanoma and identify prognostic markers that may serve as efficient clinical diagnosis and treatment selection tools.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as novel risk markers for diabetic nephropathy in patients with type 2 diabetes.

INTRODUCTION: Diabetes mellitus causes serious complications such as diabetic nephropathy. Diabetic nephropathy is now the most common reason of chronic kidney disease. Inflammation plays a crucial role in development and progression of diabetic nephropathy. The aim of this study was to evaluate the relationship of Inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) with diabetic nephropathy in Syrian patients. MATERIALS AND METHODS: A total of 158 patients with type 2 diabetes mellitus were distributed into three groups according to urinary albumin-to-creatinine ratio: Group A, type 2 diabetic patients with normoalbuminuria (urinary albumin-to-creatinine ratio <30 mg/g); Group B, type 2 diabetic patients with microalbuminuria (urinary albumin-to-creatinine ratio = 30-300 mg/g); Group C, type 2 diabetic patients with macroalbuminuria (urinary albumin-to-creatinine ratio ≥300 mg/g). Levels of inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) were recorded and compared among the three groups. RESULTS: Significant differences were detected between the groups in terms of neutrophil-to-lymphocyte ratio (p = 0.000) and platelet-to-lymphocyte ratio (p = 0.000). Receiver operating characteristic curve analysis of inflammatory markers and microalbuminuria prediction demonstrated an area under curve (AUC) of 0.869 for neutrophil-to-lymphocyte ratio (confidence interval: 0.813-0.926, p = 0.000) and 0.739 for platelet-to-lymphocyte ratio (confidence interval: 0.662-0.815, p = 0.000). CONCLUSION: Increased neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio were significantly correlated with diabetic nephropathy, and high neutrophil-to-lymphocyte ratio & platelet-to-lymphocyte ratio may be served as a predictor and a prognostic risk marker of diabetic nephropathy.