Abstract
Somatic ERBB3 hot-spot mutations promote oncogenic signaling in a subset of human tumors.
Major finding: Somatic ERBB3 hot-spot mutations promote oncogenic signaling in a subset of human tumors.
Mechanism: ERBB3 mutants cooperate with kinase-active ERBB2 to induce ligand-independent tumor growth.
Impact: Targeted therapeutics against ERBB proteins inhibit the oncogenic activity of mutant ERBB3.
Activating mutations in EGF receptor and ERBB2, members of the ERBB/HER receptor tyrosine kinase family, promote the growth and progression of many human cancers. In contrast, ERBB3, which is kinase impaired and requires heterodimerization with ERBB2 to activate signaling, is overexpressed or amplified in some tumors, but the frequency and functional impact of ERBB3 mutations in tumorigenesis are unclear. Using whole-exome sequencing of a panel of various primary human tumors, Jaiswal and colleagues identified somatic ERBB3 mutations in 12% of gastric tumors and 11% of colon tumors, including recurrent hot-spot mutations in the extracellular domain (ECD) and kinase domain. Most of these mutations mapped to regions of the ERBB3 protein that were predicted to induce conformational changes or to dysregulate ligand binding or heterodimerization, suggesting that they are functionally relevant. Expression of mutant ERBB3 alone did not induce oncogenic transformation but cooperated with ERBB2 expression to enhance the proliferation and anchorage-independent growth of colon and breast epithelial cells. Furthermore, mutant ERBB3 proteins augmented tumor growth and reduced the survival of tumor-bearing mice, whereas depletion of mutant ERBB3 impaired tumor formation. This protumorigenic function was accompanied by increased activation of downstream ERK and AKT signaling and was dependent on the kinase activity of ERBB2. In addition, expression of mutant ERBB3 in combination with ERBB2 promoted cell survival and transformation in a ligand-independent manner; a subset of ERBB3 ECD mutants was also further stimulated in response to neuregulin 1. Moreover, treatment with small-molecule inhibitors or antibodies targeting ERBB family members, particularly lapatinib, trastuzumab, and anti-ERBB3 antibodies, was effective in suppressing mutant ERBB3–mediated oncogenic activity both in vitro and in vivo. These results implicate mutant ERBB3 proteins as oncogenic drivers and suggest that they are actionable therapeutic targets.