Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic
melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on
melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic
melanoma are urgently needed. Here we report that ERBB3, a member of the
epidermal growth factor receptor family, is required for the formation of lung
metastasis from both the BI-sensitive
melanoma cell line,
MA-2, and the BI-resistant
melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of
melanoma cells in lung but is required for their further development into overt
metastases, indicating that ERBB3 might be essential for the survival of
melanoma cells after they reach the lung. Consistent with this, the ERBB3
ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both
MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic
melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor,
canertinib, significantly suppresses the
metastasis formation of BI-resistant
melanoma cell lines.