Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma.
作者： Pankita H. Pandya , Lijun Cheng , M. Reza Saadatzadeh , Khadijeh Bijangi-Vishehsaraei , Shan Tang
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摘要: 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 we employed a systems biology approach using public databases integrate CNVs, expression, survival outcomes pediatric, adolescent, young adult OS patients. Chromosome 8 was hotspot for signatures. The MYC-RAD21 gain (8q24) correlated with increased 90% the (n = 85). MYC RAD21 play role replication-stress, which is therapeutically network. We prioritized replication-stress regulators, bromodomain extra-terminal proteins (BETs), CHK1, order test hypothesis that inhibition BET + CHK1 MYC-RAD21+ pediatric models would be efficacious safe. demonstrate cell lines were sensitive (BETi) (CHK1i) at clinically achievable concentrations. While potentiation CHK1i-mediated effects by BETi BET-BRD4-dependent, BET-BRD4-independent. In xenografts, CHK1i significantly decreased tumor growth, well tolerated. Therefore, targeting replication stress promising strategy pursue as option this devastating disease.
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