FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy

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.

Authors

Institutions

Publication Details

Journal
Cancer Research
Published
2026-03-11
DOI
https://doi.org/10.1158/0008-5472.can-25-2166
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy

Tamar Y. Feinberg, Elisa de Stanchina, Trever G. Bivona, Daniel E. Gracilla et al.
Cancer Research
DNA Repair Mechanisms
article

FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy

Tamar Y. Feinberg, Elisa de Stanchina, Trever G. Bivona, Daniel E. Gracilla, Shruti Menon, Asmin Tulpule, Ann Heslin, Jonathan S. Weissman, Romel Somwar, Shruthi R. Perati, Hannah R. Allegakoen, Marcus R. Breese, Filemon S. Dela Cruz, Teresa Vizconde, Yone Phar Lin, Max A. Horlbeck, Nicholas J. Wen, Ana-Florina Galic, Marc Ladanyi, E. Alejandro Sweet-Cordero, Nicholas Everin
article en

Abstract

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.

Cancer Research
Memorial Sloan Kettering Cancer Center (US), University of California, San Francisco (US), UCSF Benioff Children's Hospital (US), Boston Children's Museum (US), Indiana University – Purdue University Indianapolis (US), University of San Francisco (US)
Alex's Lemonade Stand Foundation for Childhood Cancer, A.P. Giannini Foundation, Memorial Sloan-Kettering Cancer Center, Giannini Foundation of Agricultural Economics, National Institutes of Health, National Cancer Institute, Hyundai Hope On Wheels
Good health and well-being
Openalex Percentile: Top 25%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.