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Olaparib sensitivity is associated with cell cycle dysfunction. A) Genetic alterations including mutations and copy number alterations of DNA damage response genes (CHEK1, CHEK2, RAD51, BRCA1, BRCA2, MLH1, MSH2, ATM, ATR, MDC1, PARP1, FANCF) in TCGA ovarian serous cystadenocarcinoma (n = 585, data were downloaded from cBioPortal, http://www.cbioportal.org). B) Fisher exact test was used for the association between the mutation of DNA damage response genes and Olaparib IC50 of 24 OV cell lines from the GDSC datasets. C,D) Heatmap (C) and HRD scores (D) from unsupervised clustering of HRD gene signatures using transcriptome data of 24 OV cell lines from the DepMap Portal. Data are shown as mean ± SD (two‐tailed t‐test). E) Correlation between HRD scores and IC50 values of 24 OV cell lines from the CCLE database. Statistical correlations were analyzed by the Pearson correlation coefficient. F) Venn diagram showing the overlap of regulators of Olaparib identified by CRISPR screens, genome‐wide transcriptional data from TCGA‐OV (TCGA‐OV transcriptome_U133A‐seq database), and upregulated genes in OV from GEO dataset (GSE69428). G) Heatmap of differentially expressed genes (p < 0.05) in a cohort of HGSOCs (n = 10) compared with matched normal oviduct samples (n = 10) from the GSE69428 dataset. H) The top enriched pathways were shown using the overlapped 35 genes from Figure 1F.
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Poly (ADP‐ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here...
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Citations
... CDC7 inhibition disrupts DNA replication, increasing DNA damage and replication stress, which activates the cGAS/STING pathway and induces a type-I interferon response, boosting antitumor immunity. Combined, CDC7i and PARPi amplify DNA damage, trigger cell cycle arrest, and enhance immune activation, presenting a potent strategy for PARPi-resistant or advanced ovarian cancer (96). ...
Gynecological cancers, including cervical, ovarian, and endometrial malignancies, remain a significant global health burden, exacerbated by disparities in access to preventive measures such as HPV vaccination and routine screening. The cGAS/STING signaling pathway, a pivotal mechanism in innate immunity, detects cytosolic DNA from pathogens or cellular damage, triggering immune responses via type I interferons and inflammatory cytokines. This pathway’s dual role in gynecological cancers, either promoting antitumor immunity or facilitating tumor immune evasion, makes it a compelling target for innovative therapies. The article outlines cGAS/STING’s influence on tumor microenvironments, immune surveillance, and inflammation, with emphasis on molecular mechanisms driving cancer progression. It explores interactions between DNA damage response pathways and immune modulation, highlighting the impact of cGAS/STING activation or suppression in ovarian, cervical, and endometrial cancers. The therapeutic potential of STING agonists, PARP inhibitors, and targeted immunotherapies is reviewed, demonstrating how these approaches can boost immune responses, counteract chemotherapy resistance, and improve patient outcomes. The study also discusses strategies for leveraging cGAS/STING signaling to enhance the efficacy of immunotherapies and address tumor-mediated immune suppression, providing insights into future directions for personalized cancer treatments.