ArticleCancer research2024
AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 24 citations in OpenAlex.
- The DNA/RNA Helicase SETX Maintains R-Loop Homeostasis to Promote Chemoresistance in Ovarian Cancer.Cancer science · 2026Article
- DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.Molecular cancer therapeutics · 2026Article
- SIRT6 cooperates with KDM5C to transcriptionally silence MICAL2 and inhibit tumorigenesis in pancreatic cancer.Cell communication and signaling : CCS · 2026Article
- Ascites circRNA ASCOR Drives Platinum Resistance of High-Grade Serous Ovarian Cancer by Facilitating RPA1 Nuclear Translocation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Inhibition of PRMT5 triggers synthetic lethality in ARID1A-deficient endometrial cancer by promoting aberrant R-loop accumulation.Molecular cancer · 2026Article
- Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.Biomarker research · 2026Review
- KIF20A inhibits TRIM21-dependent ubiquitination of DHX9 to boost SOX2 stability, enhancing OSCC stemness and ferroptosis resistance.Cell death & disease · 2026Article
- Targeting WEE1 in ARID1A/TP53 Concurrent Mutant Colorectal Cancer by Exploiting R-Loop Accumulation and DNA Repair Deficiencies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Regulation of R-Loop Dynamics by Proteins and Long Noncoding RNAs: An Emerging Paradigm for Cancer Treatment.Cancer science · 2026Review
- The role of R-loop aberrations in lower-grade gliomas: prognostic, immune, and metabolic implications from multi-omics and machine learning analysis.Frontiers in immunology · 2026Article
- R‑loops in hepatocellular carcinoma: Bridging genomic instability and therapeutic opportunity (Review).Molecular medicine reports · 2026Review
- Potential Anti-Cancer Drug 6RK73 Suppresses Ovarian Cancer Growth by Inactivating the AKT1/Sp1 Induced c-Myc Signaling Pathway.Journal of Cancer · 2026Article
- Mechanisms of resistance to PARP inhibitors in advanced epithelial ovarian cancer: biological determinants and therapeutic implications.Frontiers in oncology · 2026Review
- MTUS2-AS1 suppression promotes DDX5 protein degradation to enhance the sensitivity of PARP inhibitors in BRCA-wild triple negative breast cancer.International journal of biological sciences · 2026Article
- Comprehensive identification of proteins interacting with long non-coding RNA TUG1 in R-loop regulation.Journal of biochemistry · 2025Article
- DNA/RNA-binding protein KIN17 supports esophageal cancer progression via resolving noncanonical STING activation induced by R-loop.Signal transduction and targeted therapy · 2025Article
- Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9.Journal of medicinal chemistry · 2025Article
- Identifying PSIP1 as a critical R-loop regulator in osteosarcoma via machine-learning and multi-omics analysis.Cancer cell international · 2025Article
- A Potent, Selective, Small-Molecule Inhibitor of DHX9 Abrogates Proliferation of Microsatellite Instable Cancers with Deficient Mismatch Repair.Cancer research · 2025Article
- An integrative analysis reveals cancer risk associated with artificial sweeteners.Journal of translational medicine · 2025Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. SIGNIFICANCE: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.