Targetable vulnerability of deregulated FOXM1/PLK1 signaling axis in diffuse large B cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Cell Cycle Regulation

Background:

• FOXM1 is a key regulator of cell cycle and proliferation, implicated in various cancers.
• The role of FOXM1 activation and function in diffuse large B cell lymphoma (DLBCL) remains under-investigated.
• Understanding FOXM1's significance in DLBCL is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the activation status and functional significance of the FOXM1/PLK1 axis in DLBCL.
• To identify potential therapeutic targets within the FOXM1/PLK1 signaling pathway.
• To evaluate the efficacy of targeting the FOXM1/PLK1 axis and related pathways in DLBCL models.

Main Methods:

• Proteomic analysis to assess protein expression levels and correlations.
• mRNA expression analysis to compare DLBCL with normal B cells.
• Functional studies to elucidate the mechanistic role of FOXM1/PLK1 in DNA damage response and cell cycle checkpoints.
• In vitro drug sensitivity assays using FOXM1, PLK1, ATR, and CHK1 inhibitors.

Main Results:

• FOXM1 and PLK1 protein and mRNA levels are significantly elevated in DLBCL and correlate with poor prognosis, especially in GCB-DLBCL.
• A FOXM1-PLK1 signature involving the p38-MAPK-AKT pathway, cell cycle, and DNA damage/repair was identified.
• The FOXM1/PLK1 axis plays a mechanistic role in regulating the S/G2 cell cycle checkpoint via DNA damage response pathways.
• Targeting FOXM1/PLK1 or ATR-CHK1 with small-molecule inhibitors demonstrated high efficacy in vitro DLBCL models.

Conclusions:

• The FOXM1/PLK1 axis is a critical driver in DLBCL pathogenesis and a potential prognostic biomarker.
• The identified FOXM1-PLK1 signature offers insights into DLBCL molecular mechanisms.
• Targeting the FOXM1/PLK1/ATR/CHK1 axis represents a promising therapeutic strategy for DLBCL drug discovery.