HER2 Mutant-selective

Class

small molecule

Notes

original target text: HER2 Mutant-selective Inhibitor

HER2 (also called ERBB2) is a receptor tyrosine kinase that sits on the cell surface and, upon activation, drives intracellular growth and survival signaling. In a subset of cancers, the HER2 gene itself carries activating mutations, most often small insertions in the kinase domain, that lock the receptor into a persistently active state independent of the normal ligand-binding and dimerization controls. This is mechanistically distinct from HER2 gene amplification, where cancer cells simply carry many extra copies of a normal receptor. A mutant-selective inhibitor is designed to fit the altered shape of the mutated kinase domain preferentially, blocking its aberrant signaling while interacting much more weakly with the unmutated, wild-type HER2 that is expressed at normal levels in healthy tissues such as heart, skin, and gastrointestinal lining. This selectivity is the rationale for the approach: broader HER2- or EGFR-family inhibitors that do not distinguish mutant from wild-type receptor tend to also suppress normal HER2 signaling in these tissues, producing class-related toxicities. By concentrating inhibitory activity on the oncogenic mutant form, this mechanism aims to disrupt tumor-driving signaling with less disturbance of physiological HER2 function elsewhere. This approach is relevant across tumor types where HER2 kinase-domain mutations, rather than amplification, are the driving oncogenic lesion.