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AKT1 interacts with DHX9 to Mitigate R Loop-Induced Replication Stress in Ovarian Cancer.
Huang, Tzu-Ting; Chiang, Chih-Yuan; Nair, Jayakumar R; Wilson, Kelli M; Cheng, Ken; Lee, Jung-Min.
Afiliación
  • Huang TT; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  • Chiang CY; Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
  • Nair JR; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
  • Wilson KM; Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
  • Cheng K; Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
  • Lee JM; Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Cancer Res ; 84(6): 887-904, 2024 Mar 15.
Article en En | MEDLINE | ID: mdl-38241710
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Antineoplásicos Límite: Female / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Antineoplásicos Límite: Female / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos