Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3-dependent mechanism in vitro and in vivo.

ABSTRACT: Mechanisms underlying potentiation of the anti-myeloma (MM) activity of ataxia telangiectasia Rad3 (ATR) antagonists by MAPK (Mitogen-activated protein kinases)-related extracellular kinase 1/2 (MEK1/2) inhibitors were investigated. Co-administration of the ATR inhibitor (ATRi) BAY1895344 (BAY) and MEK1/2 inhibitors, for example, cobimetinib, synergistically increased cell death in diverse MM cell lines. Mechanistically, BAY and cobimetinib blocked STAT3 Tyr705 and Ser727 phosphorylation, respectively, and dual dephosphorylation triggered marked STAT3 inactivation and downregulation of STAT3 (Signal transducer and activator of transcription 3) downstream targets (c-Myc and BCL-X_L). Similar events occurred in highly bortezomib-resistant (PS-R) cells, in the presence of patient-de

SUBMITTER: Li L 

PROVIDER: S-EPMC11650795 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature