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Exploiting WEE1 Kinase Activity as FUS::DDIT3-Dependent Therapeutic Vulnerability in Myxoid Liposarcoma
Lorena Heinst1, Kwang Seok Lee2, Ruth Berthold1
1Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany.
Purpose:
The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. As FUS::DDIT3 has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role of the cell cycle regulator WEE1 as novel FUS::DDIT3-dependent therapeutic vulnerability in MLS.
Experimental Design:
Immunohistochemical evaluation of the cell cycle regulator WEE1 was performed in a large cohort of MLS specimens. FUS::DDIT3 dependency and biological function of the G1/S cell cycle checkpoint were analyzed in a mesenchymal stem cell model and liposarcoma cell lines in vitro. WEE1 activity was modulated by RNAi-mediated knockdown and the small molecule inhibitor MK-1775 (adavosertib). An established MLS cell line-based chicken chorioallantoic membrane model was employed for in vivo confirmation.
Results:
We demonstrate that enhanced WEE1 pathway activity represents a hallmark of FUS::DDIT3-expressing cell lines as well as MLS tissue specimens and that WEE1 is required for MLS cellular survival in vitro and in vivo. Pharmacologic inhibition of WEE1 activity results in DNA damage accumulation and cell cycle progression forcing cells to undergo apoptotic cell death. In addition, our results uncover FUS::DDIT3-dependent WEE1 expression as an oncogenic survival mechanism to tolerate high proliferation and resulting replication stress in MLS. Fusion protein-driven G1/S cell cycle checkpoint deregulation via overactive Cyclin E/CDK2 complexes thereby contributes to enhanced WEE1 inhibitor sensitivity in MLS.
Conclusions:
Our preclinical study identifies WEE1-mediated replication stress tolerance as molecular vulnerability in FUS::DDIT3-driven MLS tumorigenesis that could represent a novel target for therapeutic intervention.
Insights
Targeting WEE1 kinase inhibits myxoid liposarcoma (MLS) growth by inducing DNA damage. This study reveals WEE1 as a key FUS::DDIT3-dependent vulnerability in MLS, offering a new therapeutic strategy.
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.
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