FET fusion oncoproteins disrupt physiologic DNA repair and create a targetable opportunity for ATR inhibitor therapy.

ABSTRACT: In cancers with genetic loss of specific DNA damage response (DDR) genes (i.e., BRCA1/2 tumor suppressor mutations), synthetic lethal targeting of compensatory DDR pathways has translated into clinical benefit for patients. Whether and how growth-promoting oncogenes might also create tumor-specific vulnerabilities within DDR networks is not well understood. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWSR1-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSBs), though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. We discover that EWSR1-FLI1 and other FET fusion oncoproteins are recruit

SUBMITTER: Menon S 

PROVIDER: S-EPMC10187251 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature