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A Genome-wide RNAi screen identifies combinatorial efficacy of CX-5461 with homologous recombination deficiency and Topoisomerase I inhibition in ovarian cancer
Authors
Shunfei Yan
Publication date
1 January 2019
Publisher
Abstract
© 2019 Shunfei YanHigh-grade serous ovarian cancer (HGSC) is common, with poor prognosis. Limited therapeutic options are available, and the development of new therapies is of high priority. The RNA Polymerase I (Pol I) transcription inhibitor CX-5461 has shown efficacy in both chemotherapy-sensitive and -resistant ovarian cancer through its ability to activate the DNA damage checkpoint. Here, we combine a genome-wide RNAi screening approach with a focussed drug screen to identify potential targets whose inhibition can enhance the efficacy of CX-5461. We demonstrate that CX-5461 combined with knockdown of homologous recombination DNA repair genes shows cooperative cell proliferation inhibition in several HGSC cell lines. We also demonstrate combinatorial efficacy between CX-5461 and topoisomerase 1 (TOP1) depletion or the TOP1 poison Topotecan. The combination induces cell death, cell cycle arrest and senescence even after drug withdrawal. The mechanism of their cooperativity relies on a cell cycle-independent, nucleolar DNA damage response (DDR) associated with topological stress at the ribosomal DNA and is independent of the ability to inhibit PoI I transcription or induce global replication stress. Despite dose-limiting toxicities hampering the broad use of Topotecan in the clinic, combined treatment with CX-5461 and low-dose Topotecan exhibits striking therapeutic efficacy in vivo, thus providing evidence for a novel strategy to treat HGSC
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Last time updated on 29/10/2019