Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma.

Pankita H Pandya,Barbara J Bailey,M Reza Saadatzadeh,Quinton Thompson,Jamie L Renbarger,Anthony L Sinn,Melissa A Trowbridge,Farinaz Barghi,Kathryn L Coy,Savannah Dyer,L Daniel Wurtz,Harlan E Shannon,Shan Tang,Adily Elmi,Michael J Ferguson,Jeremiah Shultz,Eric A Albright,Khadijeh Bijangi-Vishehsaraei,Sandeep Batra,Lang Li,Karen E Pollok,Mark S Marshall,Lijun Cheng,Todd Bertrand ,Courtney Young ,Junhua Ding ,Mary Ellen Murray ,Erika Dobrota

doi:10.3390/cancers12092426

Abstract

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

Highlights

High-grade osteosarcoma (OS) is the most common primary bone cancer in children, as well as in adolescents and young adults (AYA) [1,2]
Activation of the DNA damage response was evident for exposure to single-agent CHK1 inhibitors (CHK1i)/SRA737 and combination bromodomain and extra-terminal domain inhibitors (BETi)/OTX-015 + CHK1i/SRA737 increased the AKT-mediated phosphorylation of CHK1 at serine 345 p-CHK1 S345 and γH2AX. These results suggest that BETi/0TX-015-mediated effects on MYC protein levels do not represent a mechanism of action that contributes to synergistic cell-growth inhibition (Table 2) and apoptosis (Figure 5) induced by combination BETi + CHK1i in Saos2 OS cells
This study demonstrated that inhibition of BRD4 via siRNA or the BETi JQ1 increased heterochromatin protein 1 (HP1) in ovarian cancer cells which limited the DNA damage response (DDR) and increased sensitivity to CHK1i [96]

Summary

Introduction

High-grade osteosarcoma (OS) is the most common primary bone cancer in children, as well as in adolescents and young adults (AYA) [1,2]. In the last 3–4 decades, early phase clinical trials have failed to show promise for the treatment of primary OS, and the more aggressive (relapsed/refractory) form of the disease [6]. The rarity of this disease and small patient populations continue to pose a challenge for initiating new clinical trials for pediatric and AYA OS patients [7]. It is critical to understand the molecular heterogeneity and identify biomarkers within the complex genetic landscape of OS, so that actionable targets can be tested in clinical trials [3]

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