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

• DOI: 10.1158/1078-0432.c.7520321
• Publication Date: 2024-11-01T07:20:58Z
• Authors: Lorena Heinst; Kwang Seok Lee; Ruth Berthold; Ilka Isfort; Svenja Wosnig; Anna Kuntze; Susanne Hafner; Bianca Altvater; Claudia Rossig; Pierre Åman; Eva Wardelmann; Claudia Scholl; Wolfgang Hartmann; Stefan Fröhling; Marcel Trautmann
• Keywords: Myxoid liposarcoma; Wee1; Vulnerability

<div>AbstractPurpose:<p>The pathognomonic FUS::DDIT3 fusion protein drives myxoid liposarcoma (MLS) tumorigenesis via aberrant transcriptional activation of oncogenic signaling. As has so far not been pharmacologically tractable to selectively target MLS cells, this study investigated the functional role cell cycle regulator WEE1 as novel FUS::DDIT3-dependent therapeutic vulnerability in MLS.</p>Experimental Design:<p>Immunohistochemical evaluation was performed a large cohort specimens. dependency and biological function G1/S checkpoint were analyzed mesenchymal stem model lines <i>in vitro</i>. activity modulated by RNAi-mediated knockdown small molecule inhibitor MK-1775 (adavosertib). An established line–based chicken chorioallantoic membrane employed for vivo</i> confirmation.</p>Results:<p>We demonstrate that enhanced pathway represents hallmark FUS::DDIT3-expressing well tissue specimens is required cellular survival vitro</i> vivo</i>. Pharmacologic inhibition results DNA damage accumulation progression forcing cells undergo apoptotic death. In addition, our uncover expression an mechanism tolerate high proliferation resulting replication stress MLS. Fusion protein–driven deregulation overactive Cyclin E/CDK2 complexes thereby contributes sensitivity MLS.</p>Conclusions:<p>Our preclinical identifies WEE1-mediated tolerance molecular FUS::DDIT3-driven could represent intervention.</p></div>