HER2 (ErbB2), wild-type and oncogenic mutants including exon 20

Class

Type II, irreversible, brain-penetrant HER2 tyrosine kinase inhibitor (small molecule)

Pathway

HER2 receptor tyrosine kinase signaling inhibition, designed for high EGFR selectivity to avoid off-target toxicity

Notes

original target text: HER2 (ErbB2), wild-type and oncogenic mutants including exon 20 insertions

HER2 (ErbB2) is a receptor tyrosine kinase belonging to the EGFR (ErbB) family, which sits on the cell surface and, once activated, triggers intracellular signaling cascades—chiefly the RAS-MAPK and PI3K-AKT pathways—that drive cell growth, survival, and division. In a subset of cancers, HER2 is amplified, overexpressed, or altered by activating mutations such as exon 20 insertions, leading to signaling that is constitutively switched on independent of normal growth cues. This makes HER2 a rational target for inhibition: blocking its kinase activity can shut down the downstream proliferative signal in tumors that depend on it. Small-molecule tyrosine kinase inhibitors bind the kinase domain and prevent this activity; some are designed to also inhibit exon 20 mutant forms of HER2, which are often less responsive to earlier-generation agents. Selectivity for HER2 over its close relative EGFR is a deliberate design choice, since EGFR is also widely expressed in normal epithelial tissue and its inhibition causes skin and gastrointestinal toxicity. Brain penetration is another design consideration, since HER2-driven cancers frequently metastasize to the central nervous system. This mechanism is broadly relevant to breast, gastric, and lung cancers driven by HER2 alterations.