Driving cancer through ErbB3

Roche's Genentech Inc. unit has shown that mutations in ERBB3 can drive oncogenesis by enhancing the receptor's ability to form a heterodimer with HER2.1 Because the process appears to depend on HER2, the results suggest existing HER2-targeted therapies could also be effective in cancers driven by mutations in ERBB3.

Epidermal growth factor receptor 3 (EGFR3; HER3; ErbB3) is a member of the ErbB family of receptor tyrosine kinases. The membrane-bound receptor is comprised of an extracellular domain (where ligand binding and dimerization interactions occur), an a-helical transmembrane segment and an intracellular tyrosine kinase domain to phosphorylate downstream targets.

Unlike other members of the ErbB family, ErbB3's kinase domain is impaired and does not show significant kinase activity on its own.2 To activate downstream cellular signaling pathways via phosphorylation, a ligand such as neuregulin 1 (NRG1) must first bind to ErbB3's extracellular domain.3

This ligand binding promotes the formation of a heterodimer between ErbB3 and other members of the ErbB family, such as HER2 (EGFR2; ErbB2; neu), which have functional kinase domains.4,5

"We noticed that there were recurrent mutations in ERBB3 in the context of colon and gastric cancers, although the functional relevance of such mutations was unclear," said Somasekar Seshagiri, a principal scientist in molecular biology at Genentech. "We were especially curious about

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