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

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 0372544 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2141 (Electronic) Linking ISSN: 00071048 NLM ISO Abbreviation: Br J Haematol Subsets: MEDLINE

Publication: Oxford : Wiley-Blackwell
Original Publication: Oxford : Blackwell Scientific Publications

STAT3 Transcription Factor*/metabolism ; Ataxia Telangiectasia Mutated Proteins*/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins*/metabolism ; Multiple Myeloma*/drug therapy ; Multiple Myeloma*/pathology ; Multiple Myeloma*/metabolism ; MAP Kinase Kinase 1*/antagonists & inhibitors ; MAP Kinase Kinase 1*/metabolism; Humans ; Animals ; Mice ; Cell Line, Tumor ; MAP Kinase Kinase 2/antagonists & inhibitors ; MAP Kinase Kinase 2/metabolism ; Azetidines/pharmacology ; Xenograft Model Antitumor Assays ; Protein Kinase Inhibitors/pharmacology ; Piperidines/pharmacology ; Mice, SCID ; Cell Death/drug effects ; Drug Synergism

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-derived conditioned medium, and with alternative ATR (e.g. M1774) and MEK1/2 (trametinib) inhibitors. Notably, constitutively active STAT3 c-MYC or BCL-X L ectopic expression significantly protected cells from BAY/cobimetinib. In contrast, transfection of cells with a dominant-negative form of STAT3 (Y705F) sensitized cells to cobimetinib, as did ATR shRNA knockdown. Conversely, MEK1/2 knockdown markedly increased ATRi sensitivity. The BAY/cobimetinib regimen was also active against primary CD138 ⁺ MM cells, but not normal CD34 ⁺ cells. Finally, the ATR inhibitor/cobimetinib regimen significantly improved survival in MM xenografts, including bortezomib-resistant models, with minimal toxicity. Collectively, these findings suggest that combined ATR/MEK1/2 inhibition triggers dual STAT3 Tyr705 and Ser727 dephosphorylation, pronounced downregulation of cytoprotective targets and MM cell death, warranting attention as a novel therapeutic strategy in MM.
(© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

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5UM1CA186644 NIH/NCI; P30 CA16059 NIH/NCI; CA205607 NIH/NCI

Keywords: ATR inhibitor; STAT3; multiple myeloma

0 (STAT3 Transcription Factor)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 2.7.11.1 (ATR protein, human)
0 (STAT3 protein, human)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.12.2 (MAP Kinase Kinase 2)
0 (Azetidines)
EC 2.7.12.2 (MAP2K1 protein, human)
0 (Protein Kinase Inhibitors)
ER29L26N1X (cobimetinib)
EC 2.7.1.- (MAP2K2 protein, human)
0 (Piperidines)

Date Created: 20241008 Date Completed: 20241212 Latest Revision: 20241212

20241213

10.1111/bjh.19796

39379134