Khadija Banu, Mohammad Aslam Khan, Sihan Li, Morgan Reynolds-Gagliano, Xiaofei Wang, Robert J. Mobley, Kelly R. Barnett, Matthew M. Wielgosz, Matthew Bauler, Christopher Wincek, Kiran Kodali, W Wang, Vishwajeeth Pagala, Anthony A. High, Daniel Putnam, Rishi S. Kotecha, Laurence C. Cheung, X X, Robert E. Throm, Shondra M Pruett-Miller, Daniel Savic, Samuel W. Brady
Cancer therapeutics frequently fail in clinical trials because of poor therapeutic index (efficacy-to-toxicity ratio). We systematically identified targets likely to have a good therapeutic index, revealing insulin receptor substrate 4 (IRS4) as a dependency in IRS4 -expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed IRS4 expression consistent with dependency in 68% of choroid plexus, 37% of malignant rhabdoid, 31% of NUT midline, and 5% of osteosarcomas, while in adult cancers, it was expressed in 8% of uterine leiomyosarcomas and 1 to 2% of lung squamous, stomach, and breast carcinomas. IRS4 expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent GATA3-IRS4 and ANKRD30A-IRS4 in breast cancer, while rhabdoid and NUT midline cancers expressed IRS4 epigenetically. IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.