In cancers with genetic loss of specific DNA damage response (DDR) genes (e.g., BRCA1/2 tumor suppressor mutations), synthetic lethal targeting of compensatory DDR pathways has translated into clinical benefit for patients. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSBs), and FET fusion oncoproteins drive a diversity of sarcomas and leukemias. A better understanding of the function of both native FET proteins and FET fusion oncoproteins in DNA repair could reveal tumor-specific vulnerabilities and provide therapeutic opportunities. Focusing on Ewing sarcoma, a pediatric bone tumor driven by the FET fusion oncoprotein EWSR1::FLI1, as a model for FET rearranged cancers, we discovered here that recruitment of EWSR1::FLI1 and other FET fusion oncoproteins to DNA DSBs impairs the activation and downstream signaling of the DNA damage sensor ATM. The compensatory ATR signaling axis acts as a collateral dependency and therapeutic target in patient-derived xenograft models of multiple FET rearranged cancers. In summary, these findings describe how oncogenes can disrupt physiologic DNA repair and provide the preclinical rationale for testing ATR inhibitors in FET rearranged cancers as part of ongoing early phase clinical trials.
Gracilla et al. (Wed,) studied this question.