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Updated: May 1, 2026

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
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Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog

Published on: November 5, 2014

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

Khadija Banu1, Mohammad Aslam Khan1, Sihan Li1

  • 1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Science Advances
|April 29, 2026
PubMed

Insights

Insulin receptor substrate 4 (IRS4) is a novel cancer dependency identified in various pediatric and adult cancers. Targeting IRS4 may offer a new therapeutic strategy for cancers expressing this protein.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cancer therapeutics often fail due to a poor therapeutic index (efficacy-to-toxicity ratio).
  • Identifying novel cancer-specific dependencies is crucial for developing effective treatments.

Purpose of the Study:

  • To systematically identify potential therapeutic targets with a favorable therapeutic index.
  • To investigate the role of insulin receptor substrate 4 (IRS4) as a dependency in cancers.

Main Methods:

  • Pan-cancer analysis of pediatric and adult tumor datasets to assess IRS4 expression.
  • Analysis of genomic alterations (enhancer hijacking) and epigenetic modifications associated with IRS4 expression.
  • Functional analysis of IRS4 in cancer dependency and pathway activation (PI3K-Akt).
  • Domain analysis of IRS4 to predict drug targeting strategies.

Main Results:

  • IRS4 was identified as a dependency in IRS4-expressing cancers, particularly in pediatric-enriched cancers like choroid plexus (68%) and malignant rhabdoid (37%).
  • Adult cancers with IRS4 expression included uterine leiomyosarcomas (8%) and low percentages of lung, stomach, and breast carcinomas.
  • IRS4 expression was linked to enhancer hijacking rearrangements (e.g., GATA3-IRS4) in breast cancer and epigenetic regulation in rhabdoid and NUT midline cancers.
  • IRS4 promotes cancer dependency via PI3K-Akt activation; dispensable domains suggest degradation-based targeting.

Conclusions:

  • IRS4 is a validated therapeutic target in cancers exhibiting IRS4 dependency.
  • The findings suggest that IRS4-targeting strategies, potentially using degradation-based modalities, could be effective in treating specific cancer types.

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