Miguel Bronchud, Medical Oncologist at GenesisCare Corachán in Barcelona, shared on LinkedIn:
“Efficient search of druggable targets in rare pediatric cancers?
IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors
By: KHADIJA BANU et al (2026)
Interesting research project published in SCIENCE by the St Jude’s Institute in Memphis (Saint of the Lost Causes) and American Lebanese Syrian Associated Charities
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.
Insulin receptor substrate 4 (IRS4) is not a nice gene to have over expressed in your cells- it can act as a constitutively active oncogenic driver that hyperactivates cell growth pathways independently of normal upstream signals, promoting tumor progression and therapeutic resistance.
Title: IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors
Authors: 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, Wei Wang, Vishwajeeth Pagala, Anthony A. High, Daniel Putnam, Rishi S. Kotecha, Laurence C. Cheung, Xiaotu Ma, Robert E. Throm, Shondra M. Pruett-Miller, Daniel Savic, Samuel W. Brady.
IRS4 is a cytoplasmic docking protein that normally remains repressed in most adult tissues.When abnormally expressed or mutated, it acts as a platform that activates key cancer-promoting cascades- among them the PI3K/AKT/mTOR and Ras/MAPK pathways, driving cell proliferation and survival without needing external hormone signals like insulin or IGF-1.
Pan-cancer analysis of pediatric-enriched cancers revealed IRS4expression 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 only 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.
In other words, just 3 to 15% of anticancer therapeutics entering phase 1 clinical trials ultimately become US Food and Drug Administration (FDA) approved which is the lowest rate among major diseases. But guessing the right drug targets and protein pockets within those 3D targets would make it a lot easier for effective drug development.
This challenge is partly because cancer relies on therapeutic targets that are also found in normal cells, given that cancer arises from normal tissues.
The ability of a therapy to reduce tumor burden while minimizing toxicity is conceptualized as the ‘therapeutic index’, with a high index indicating strong antitumor efficacy and low normal-tissue toxicity.”
Other articles about Pediatric Cancer on OncoDaily.