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 PARPi-resistant BRCAm HGSOC patients, and high co-expression 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.
Congratulations to Professor Jung-Min Lee from NIH (National Institutes of Health) for their excellent work published in Cancer Res (IF=12.7)!
InvivoChem is proud to provide Professors Farshad Nassiri and Gelareh Zadeh with our high-quality product Olaparib (Cat #: V0300, PARP inhibitor) for this research.
References: Cancer Res. 2024 Jan 19. doi: 10.1158/0008-5472.CAN-23-1908.
