HER2 (ERBB2) exon 20 insertions and point mutations; also

Class

Oral HER2/EGFR tyrosine kinase inhibitor (sevabertinib)

Pathway

HER2/EGFR signal transduction inhibition

Notes

original target text: HER2 (ERBB2) exon 20 insertions and point mutations; also mutant-selective EGFR

HER2 (also called ERBB2) and EGFR are related receptor tyrosine kinases embedded in the cell membrane. Normally they are activated by growth factor binding, which triggers dimerization and autophosphorylation, switching on intracellular signaling cascades—chiefly RAS/MAPK and PI3K/AKT—that drive cell proliferation and survival. In certain cancers, small insertions in exon 20 of the HER2 or EGFR gene, or specific point mutations, lock the kinase domain into an active configuration without requiring growth factor stimulation. This produces continuous, unregulated proliferative signaling that behaves as an oncogenic driver, most notably in subsets of non-small cell lung cancer. Because these mutations create a structurally distinct kinase pocket compared with wild-type receptors, a rationally designed small-molecule inhibitor can be built to selectively engage the mutant conformation. Targeting both HER2 and EGFR exon 20 variants with one agent addresses the biological reality that these two genes are closely related paralogs producing analogous insertion mutations, so a single molecule with activity against both can address a broader population of tumors driven by this mechanism than an agent restricted to only one receptor. Mutant selectivity is also pursued to spare the wild-type receptor population that performs normal physiological functions in skin and gut tissue, which is relevant to the tolerability of this drug class.