Exploiting WEE1 Kinase Activity as FUS::DDIT3-Dependent Therapeutic Vulnerability in Myxoid Liposarcoma

Area of Science:

• Oncology
• Molecular Biology
• Cell Cycle Regulation

Background:

• Myxoid liposarcoma (MLS) is driven by the FUS::DDIT3 fusion protein, which activates oncogenic pathways.
• Targeting FUS::DDIT3 directly has proven challenging, necessitating the identification of alternative therapeutic vulnerabilities.
• The cell cycle regulator WEE1 is investigated as a potential target in MLS.

Purpose of the Study:

• To investigate the functional role of WEE1 in FUS::DDIT3-driven MLS.
• To determine if WEE1 inhibition represents a novel therapeutic vulnerability in MLS.
• To explore the mechanism by which WEE1 contributes to MLS cell survival.

Main Methods:

• Immunohistochemical evaluation of WEE1 in MLS specimens.
• Analysis of WEE1 dependency and G1/S cell cycle checkpoint function in cell models.
• Modulation of WEE1 activity using RNAi and the inhibitor MK-1775 (adavosertib).
• In vivo validation using a chicken chorioallantoic membrane model.

Main Results:

• Enhanced WEE1 pathway activity is a hallmark of MLS and is required for cell survival.
• WEE1 inhibition leads to DNA damage, cell cycle arrest, and apoptosis.
• FUS::DDIT3 drives WEE1 expression as a survival mechanism to tolerate replication stress.
• Deregulation of the G1/S checkpoint via Cyclin E/CDK2 contributes to WEE1 inhibitor sensitivity.

Conclusions:

• WEE1 inhibition is a promising therapeutic strategy for FUS::DDIT3-driven MLS.
• WEE1-mediated replication stress tolerance is a key molecular vulnerability in MLS.
• Targeting WEE1 offers a novel approach for MLS treatment.