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Supplementary Fig. S1 from AKT1 interacts with DHX9 to Mitigate R Loop–Induced Replication Stress in Ovarian Cancer

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posted on 2024-03-15, 07:21 authored by Tzu-Ting Huang, Chih-Yuan Chiang, Jayakumar R. Nair, Kelli M. Wilson, Ken Cheng, Jung-Min Lee

Supplementary Fig. S1

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE 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. 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