IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors.

Abstract

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 <i>IRS4</i>-expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed <i>IRS4</i> 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. <i>IRS4</i> expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent <i>GATA3-IRS4</i> and <i>ANKRD30A-IRS4</i> in breast cancer, while rhabdoid and NUT midline cancers expressed <i>IRS4</i> 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.