Journal Article

HER2 missense mutations have distinct effects on oncogenic signaling and migration

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

2015

Overview

SignificanceThe discovery of human epidermal growth factor receptor 2 (HER2) missense mutations in breast and other cancers potentially make such tumors susceptible to current and future HER2-targeted therapies. However, the majority of HER2 mutations occur in HER2 nonamplified cancers, and whether these mutations will predict for sensitivity to HER2-directed therapies remains unknown. Using genome editing, the data presented here suggest that HER2 missense mutations are functionally distinct and require additional oncogenic input to impart cancerous phenotypes. These results suggest that HER2 missense mutations by themselves may not be reliable predictors of response to HER2-targeted therapies, a hypothesis currently being tested in genomically driven clinical trials. 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.

• Publisher: National Academy of Sciences
• Subject: Biological Sciences / Blotting, Western / Breast cancer / Cell Line, Tumor / Cell Movement - genetics / Cell Proliferation - physiology / Cells / Colony-Forming Units Assay / Epidermal growth factor / Flow Cytometry / Gene Targeting / HEK293 Cells / Humans / Immunoblotting / Immunohistochemistry / Lapatinib / Medical Sciences / Medical treatment / Mutation / Mutation, Missense - genetics / Neoplasms - genetics / PNAS Plus / Quinazolines / Quinolines / Receptor, ErbB-2 - genetics / Signal Transduction - genetics / Thiazoles