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 | 
Jun 06, 2013
 |  BC Innovations  |  Cover Story

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 these mutations in ERBB3, as it is the only member of the ErbB family that by itself does not show significant kinase activity. Thus, we sought to find out why cancer patients still accumulate recurrent somatic mutations in ERBB3 when the protein is not able to phosphorylate and activate downstream targets on its own."

Now, Seshagiri's group has characterized the functional relevance of protein-altering somatic mutations in ERBB3 and also assessed the frequency of such mutations across a range of cancers.

Whole-exome sequencing of 507 human primary tumor samples covering 20 types of cancer foundERBB3 mutations in 12% of gastric cancer samples, 11% of colon cancer samples and occurring sporadically in samples of other cancer types. The majority of the mutations occurred in the receptor's extracellular domain.

In mouse and human cell lines, most of the cancer-associated ErbB3 mutants tested by the group promoted oncogenic transformation and signaling but only when co-expressed with functional HER2. In cells that expressed mutant ErbB3, antibody-mediated neutralization of NRG1 did not significantly affect cell survival or impair the mutant receptor's ability to form a heterodimer with HER2.

The latter result suggests that oncogenic mutations in the receptor enhance its ability...

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