Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism.

ABSTRACT: Aberrant activation of multiple complex signaling pathways underlies the pathogenesis of rhabdomyosarcoma (RMS), which remains a cause of mortality in approximately 30% of children with RMS. Bromodomain and extraterminal (BET) domain chromatin remodeling regulates several of these pathways. Here, we targeted bromodomain 4 (BRD4) in combination with another molecular metabolic tumor driver, the Akt/mTOR signaling pathway, to provide a highly effective treatment for this neoplasm. We demonstrated that a nexus of these two molecular pathways underlies RMS pathogenesis. Our data show that the combined inhibition of the BET bromodomain and mTORC1/2 signaling abrogates aggressive RMS growth. Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC

SUBMITTER: Srivastava RK 

PROVIDER: S-EPMC9262843 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature