A Genome-wide RNAi screen identifies combinatorial efficacy of CX-5461 with homologous recombination deficiency and Topoisomerase I inhibition in ovarian cancer
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusOpen Access
© 2019 Shunfei Yan
High-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.
KeywordsCX-5461; RNA polymerase I; Topoisomerase I; BRCA2; high-throughput screen; synergistic effects; drug combination; high-grade serous ovarian cancer; homologous recombination; DNA damage response
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