Abstract

Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival. BRD4 inhibition increased CBX5 (HP1α) level. CHK1 inhibitor induced DDR marker, γ-H2AX, but BRD4 suppression did not. Furthermore, nuclear localization of CBX5 and γ-H2AX was mutually exclusive in BRD4-and CHK1-inhibited cells, suggesting BRD4 facilitates DDR by repressing CBX5. Our results provide a strong rationale for clinical investigation of CHK1 and BRD4 co-inhibition, especially for HGSOC patients with BRD4 overexpression.

Highlights

  • Ovarian cancer (OC) is the most aggressive gynecological malignancy, with nearly 15,000 deaths in USA annually

  • We found that siRNAs targeting Bromodomain containing 4 (BRD4), MAP3K7, and NLK increased the cytotoxicity of CHK1 inhibitor (CHK1i) in all 5 cell lines (Supplementary Table 1) [6]

  • We further focused on Bromodomain containing 4 (BRD4) due to its translational potential and confirmed this screening result by an independent siBRD4

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Summary

Introduction

Ovarian cancer (OC) is the most aggressive gynecological malignancy, with nearly 15,000 deaths in USA annually. Comprehensive genomic approaches identified molecular alterations in cancer, intended to enable precision medicine in which patients are selected for specific treatments based on molecular parameters. This strategy is expected to improve outcome for patients over empiric chemotherapy. Relapse suggests that OC cells adapt to overcome DNA damage Supporting this notion, we previously identified that checkpoint kinase 1 (CHEK1 or CHK1) was overexpressed in most cases of HGSOC at the time of initial diagnosis, as compared to normal ovarian surface epithelium [2]. LY2606368 is a potent CHK1 inhibitor (CHK1i) with anti-tumor activity [3, 4] This agent is currently in clinical trials for many cancers, including our phase 2 study for women with HGSOC (NCT02203513)

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