Inhibiting FOXM1 Sensitizes Myeloma Cells to BCL2 Inhibitor Venetoclax By Repressing MYC Pathway

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.1950-1950
• Main Authors: Zhou, Vivian, Moat, Luke, Yu, Manya, Parashar, Deepak, Shour, Abdul, Zhang, Liang, Kitchner, Terrie, Shukla, Sanjay, Guo, Song, Ananiev, Gene, Katzenellenbogen, Benita S., Katzenellenbogen, John, Onitilo, Adedayo, Janz, Siegfried, Wen, Zhi
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-180268

Background: Despite improved 5-year survival in multiple myeloma (MM), relapsed and/or refractory multiple myeloma (RRMM) remains a big challenge. Forkhead box transcription factor FOXM1 is a key regulator of metabolism and cell cycle progression in RRMM. FOXM1 is highly expressed in OPM2 and Delta47 cells compared to 9 other myeloma cell lines. Inhibiting FOXM1 function by deleting the FOXM1 gene or using the small-molecule FOXM1 inhibitor, NB73, suppresses OPM2 and Delta47 cells in vitro and in vivo. We hypothesized that FOXM1-targeted inhibition of RRMM may be deepened by combining NB73 with established or candidate myeloma drugs. Materials and methods: We used 3 tools to develop FOXM1-targeted combinatorial therapies by: (1) combining NB73 with 6 widely used myeloma drugs; (2) repurposing screens of cancer drugs in FOXM1-knockout (FOXM1 KO) vs FOXM1-proficient (FOXM1 WT) OPM2 cells; and (3) combining NB73 with compounds recommended by CMap analysisof FOXM1 KO vs FOXM1 WTcells. RNA seq analysis was used to elucidate pathways underlying drug synergy. Results: We adopted ZIP drug synergy scoring assay to examine the interactions between NB73 and the 6 myeloma drugs in MM cells. ZIP score takes the merits of both Loewe score that appraises drugs targeting the same pathway and Bliss score that appraises drugs targeting different pathways. Venetoclax, a BCL2 inhibitor treating MM with t(11;14) translocation, synergized with NB73 in killing OPM2 and Delta47 cells. In contrast, taking advantage of FOXM1 WT and FOXM1 KO MM cells, we conducted repurposing screens of FDA-approved anti-cancer drug library (NCI AOD X) in these cells. We identified Dasatinib and Panobinostat that killed FOXM1 KO OPM2 cells much more than FOXM1 WT cells. We also identified 3 drugs from the repurposing screens in FOXM1 WT and FOXM1 KO Delta47 cells. Thirdly, CMap, a large-scale compendium of functional perturbations in cultured human cells coupled to a gene expression read-out, implicated a synergy between NB73 and Thapsigargin that was verified by ZIP drug synergy scoring assay. Collectively, we have identified a total of 7 drugs (6 FDA-approved) synergizing with NB73 in killing OPM2 and/or Delta47 cells in which FOXM1 is highly expressed. Since Venetoclax is a current myeloma drug, we have focused on how inhibiting FOXM1 sensitizes MM cells to Venetoclax. Firstly, we showed the synergy between NB73 and Venetoclax in inducing apoptosis in OPM2 and Delta47 cells. We used the experimen