Mechanisms Of JQ1 Resistance And THZ1 Action In Ovarian Cancer

Objective: BET bromodomain inhibitors show promising efficacy for the treatment of ovarian cancer by downregulating pivot transcription factors.In this study,we systematically determined the molecular mechanisms of BET inhibitor resistance in ovarian cancer,and the potential antitumor activities of other epigenetic or transcriptional therapies.Methods: Multiple JQ1-resistant ovarian cancer cell lines were generated and characterized.We performed an unbiased high-throughput drug screen and identified a candidate compound with antineoplastic effect——THZ1.We verified its effect biologically by the use of technologies like western blot analysis and genome-editing technique.The molecular underpinnings of inhibitor potency were further investigated using Ch IP-seq and RNA-seq.Results: JQ1-resistant cells displayed increased levels of chromatin-bound BRD4.THZ1 was identified as a new transcription-targeting compound that antagonized JQ1 resistance and exerted broad cytotoxicity against ovarian tumors.Mechanistically,CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer and CDK7 inhibition led to a pronounced disregulation of gene transcription,with a preferential repression of E2F-regulated gene sets and transcripts associated with super-enhancers.Conclusions: Our findings revealed the molecular mechanisms of JQ1 resistance and THZ1 action in ovarian cancer,and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in ovarian cancer.