Insulin receptor substrate 4 (IRS4) is a constitutive active oncogenic driver collaborating with HER2 and causing therapeutic resistance.

Insulin receptor substrate 4 (IRS4) belongs to a family of cytoplasmic docking proteins mediating signals from cell surface receptors to downstream effectors. While IRS1 and IRS2 mediate signals from an active receptor, we found that IRS4 hyperactivates the phosphatidylinositol phosphate kinase (PI3K)-pathway independent of upstream signals and is irresponsive to feedback regulation causing cancer and resistance to human epidermal growth factor receptor 2 (HER2) targeted therapy.