HER2 missense mutations have distinct effects on oncogenic signaling and migration

Daniel J. Zabransky, Christopher L. Yankaskas, Rory L. Cochran, Hong Yuen Wong, Sarah Croessmann, David Chu, Shyam M. Kavuri, Monica Red Brewer, D. Marc Rosen, W. Brian Dalton, Ashley Cimino-Mathews, Karen Cravero, Berry Button, Kelly Kyker-Snowman, Justin Cidado, Bracha Erlanger, Heather A. Parsons, Kristen M. Manto, Ron Bose, Josh LauringCarlos L. Arteaga, Konstantinos Konstantopoulos, Ben Ho Park

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as "negative" by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-Amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, 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 of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.

Original languageEnglish
Pages (from-to)E6205-E6214
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number45
DOIs
StatePublished - Nov 10 2015

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    Zabransky, D. J., Yankaskas, C. L., Cochran, R. L., Wong, H. Y., Croessmann, S., Chu, D., Kavuri, S. M., Brewer, M. R., Marc Rosen, D., Brian Dalton, W., Cimino-Mathews, A., Cravero, K., Button, B., Kyker-Snowman, K., Cidado, J., Erlanger, B., Parsons, H. A., Manto, K. M., Bose, R., ... Park, B. H. (2015). HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proceedings of the National Academy of Sciences of the United States of America, 112(45), E6205-E6214. https://doi.org/10.1073/pnas.1516853112