HER2missense mutations have distinct effects on oncogenic signaling and migration

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-11, Vol.112 (45), p.E6205-E6214
• Main Authors: Zabransky, Daniel J., Yankaskas, Christopher L., Cochran, Rory L., Wong, Hong Yuen, Croessmann, Sarah, Chu, David, Kavuri, Shyam M., Brewer, Monica Red, Rosen, D. Marc, Dalton, W. Brian, Cimino-Mathews, Ashley, Cravero, Karen, Button, Berry, Kyker-Snowman, Kelly, Cidado, Justin, Erlanger, Bracha, Parsons, Heather A., Manto, Kristen M., Bose, Ron, Lauring, Josh, Arteaga, Carlos L., Konstantopoulos, Konstantinos, Park, Ben Ho
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490

Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence ofHER2gene amplification such that mostHER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplifiedHER2missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment ofHER2gene-amplified breast cancers. Here we functionally characterizeHER2kinase and extracellular domain mutations through gene editing of the endogenous loci inHER2nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority ofHER2missense mutations do not impart detectable oncogenic changes. However, theHER2V777L mutation increased biochemical pathway activation and, in the context of aPIK3CAmutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting ofHER2missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis ofHER2mutations and strategies to target them.