Introduction 

In ovarian cancer (OC), resistance to therapies and treatment toxicity underscores the urgent need for innovative interventions. Around 30% of high-grade serous ovarian carcinoma (HGSOC) exhibit alteration in the bromodomain-containing protein 4 (BRD4) gene and/or have amplification of the cyclin-E1 (CCNE1) gene. Over 57% of ovarian clear cell carcinoma (OCCC) have a loss of function of ARID1A gene and 23% overexpress CCNE1. These genetic changes offer potential therapeutic targets for Bromodomain and Extra-Terminal motif inhibitors (BETi) and DNA damage checkpoint inhibitors (DDCi). Despite their synergistic effects in preclinical models of both OC subtypes, clinical trials reveal substantial patient toxicity. The recent emergence of a less toxic DDCi, PKMYT1i, has sparked interest in exploring its combined use with BETi. 

Methods 

A panel of human OCCC and HGSOC cell lines was treated with BRD2/BRD4 inhibitor AZD5153 in combination with different DDCi (ATRi: AZD6738, WEE1i: adavosertib, PKMYT1i: RP-6306). Clones from genetically engineered murine syngeneic model Trp53-/-, representative of HGSOC, were used to investigate the contribution of specific oncogenes to the response to BETi and DDCi combination.  

Results 

Although PKMYT1i monotherapy was only lethal in CCNE1 amplified cell lines, the combination with AZD5153 was synergistic in 82% of the cell lines. Using the Trp53-/- clones, we determined that the synergism is independent of the HR status or Ccne1 level of expression, suggesting a broader therapeutic potential of this drug combination. The synergism observed with other DDCi in combination with AZD5153 was similar, indicating shared mechanisms of synergism.  

Conclusions 

This study demonstrates the synergistic activity between BETi and PKMYT1i in OC cells. Future investigation will be needed to assess the toxicity of this combination in mouse and human. This combination hold promises for improving OC treatment outcomes and patient survival.