1. AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.
- Author
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Huang TT, Chiang CY, Nair JR, Wilson KM, Cheng K, and Lee JM
- Subjects
- Humans, Female, R-Loop Structures, Proto-Oncogene Proteins c-akt metabolism, Drug Resistance, Neoplasm genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Carcinoma, Ovarian Epithelial drug therapy, Protein Kinase Inhibitors pharmacology, Neoplasm Proteins metabolism, DEAD-box RNA Helicases genetics, DEAD-box RNA Helicases metabolism, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Antineoplastic Agents pharmacology
- 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., (©2024 American Association for Cancer Research.)
- Published
- 2024
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