Ferroptosis is a special form of cell death with extensive biological associations with various cancers; however, the role of aberrantly expressed ferroptosis-related long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) remains unclear. To explore the role and prognostic value of ferroptosis-related lncRNAs in HCC and to screen potential therapeutic targets. The RNA-seq data for 424 HCC patients and clinical data for 377 HCC patients were obtained from The Cancer Genome Atlas (TCGA) and evaluated using the Pearson's test to identify differentially expressed lncRNAs. The univariate analysis, least absolute shrinkage and selection operator Cox regression analysis were performed to construct and validate a prognostic risk-score model. The prognostic capacity was evaluated using the Kaplan-Meier method, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve analyses. The enrichment analysis was performed to explore the functions of ferroptosis-related lncRNAs from the perspective of tumor immunology. Seventeen differentially expressed lncRNAs were identified (AL139384.1, AL928654.1, MKLN1-AS, AC145207.8, LINC00205, ZFPM2-AS1, LINC00942, POLH-AS1, AC090772.3, AL603839.3, AC012073.1, AC099850.1, AC026401.3, AP001469.3, AL031985.3, SNHG10, SNHG21) to establish the risk-score model. Survival analyses demonstrated poorer survival in high-risk patients, and the risk score was shown to be a better independent prognostic factor than conventional clinical characteristics. Additionally, we found close correlations between the risk score and immune cell subpopulation functions, as well as between the expression of immune checkpoint and carcinogenic N6-methyladenosine (m6A)-related mRNAs. The novel ferroptosis-related lncRNA signature may serve as an individualized prognostic prediction tool for patients with HCC.

BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.

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. 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. 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. 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.

The development of poly (ADP-ribose) polymerase inhibitors (PARPis) is widely considered a therapeutic milestone in the management of BRCA1/2-deficient malignancies. Since a growing number of cancer treatment guidelines include PARPis, the inevitably emerging PARPi resistance becomes a serious limitation that must be addressed. Targeting the DNA damage response signaling kinase, ATR (ataxia telangiectasia and rad3-related serine/threonine kinase), activated in response to PARPi-induced replication stress, represents a promising approach in fighting PARPi-resistant cancers. The success of this combination therapy in preclinical models has inspired efforts to translate its potential through extensive clinical research and clinical trials. However, the available clinical evidence suggests that PARPi/ATRi combinations have yet to reach their anticipated therapeutic potential. In this review, we summarize work elucidating mechanisms underpinning the effectiveness of ATRi in fighting PARPi resistance and review translational studies reporting efficacy in different types of cancer. Finally, we discuss potential biomarkers of patient selection for customized combinations of PARPi/ATRi treatments.

DNA double‐strand breaks (DSBs) generated from collisions of DNA replication forks with cisplatin‐induced interstrand crosslinks underpin cisplatin cytotoxicity. Yet, the impact of cell‐cycle‐dependent cisplatin–DNA adduct (CDA) formation on cell cycle progression and interactions with DNA replication remain incompletely characterized. Also, although cisplatin enhances tumor response to ionizing radiation (IR), the underpinning radiosensitizing mechanisms remain unresolved. Here, we close this void and analyze CDAs (GpG crosslinks) and DSB (γH2AX foci) induction and repair in a strictly cell‐cycle‐dependent manner. We report for the first time that CDAs form in a dose‐ and time‐dependent manner in all cell cycle phases, whereas DSBs emerge only in S‐phase. Repair of IR‐induced DSBs remains largely unaffected by CDAs in G ₁ , S, and G ₂ phases, but is inhibited when S‐phase‐treated cells progressed to G ₂ . Radiosensitization occurs after prolonged cisplatin exposure, likely owing to G ₂ ‐phase accumulation and lesion evolution from S‐phase, thus impairing repair of IR‐induced DSBs. Cisplatin fails to radiosensitize quiescent (G ₀ ) cells. In summary, CDA formation is similar across the cell cycle, but DSBs form only in S‐phase. Whereas CDAs fail to interfere with repair of IR‐induced DSBs, progression‐dependent repair disruptions cause radiosensitization. Elucidation of the underpinning mechanisms may help to design improved cisplatin–radiation schedules for more efficacious therapies.