Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors.

ABSTRACT: Inhibitors of the bromodomain and extra-terminal domain (BET) family proteins modulate EWS-FLI1 activities in Ewing sarcoma. However, the efficacy of BET inhibitors as a monotherapy was moderate and transient in preclinical models. The objective of this study was to identify the mechanisms mediating intrinsic resistance to BET inhibitors and develop more effective combination treatments for Ewing sarcoma. Using a panel of Ewing sarcoma cell lines and patient-derived xenograft lines (PDX), we demonstrated that IGF1R inhibitors synergistically increased sensitivities to BET inhibitors and induced potent apoptosis when combined with BET inhibitors. Constitutively activated AKT significantly protected Ewing sarcoma cells against BET inhibitors, suggesting that IGF1R regulates responsiveness to

SUBMITTER: Loganathan SN 

PROVIDER: S-EPMC6497538 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature