Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity
- Authors
- Hanker, Ariella B.; Brown, Benjamin P.; Meiler, Jens; Marin, Arnaldo; Jayanthan, Harikrishna S.; Ye, Dan; Lin, Chang-Ching; Akamatsu, Hiroaki; Lee, Kyung-Min; Chatterjee, Sumanta; Sudhan, Dhivya R.; Servetto, Alberto; Brewer, Monica Red; Koch, James P.; Sheehan, Jonathan H.; He, Jie; Lalani, Alshad S.; Arteaga, Carlos L.
- Issue Date
- Aug-2021
- Publisher
- CELL PRESS
- Keywords
- breast cancer; HER2; HER3; molecular dynamics; neratinib; personalized structural biology; PI3K; precision oncology; Rosetta
- Citation
- CANCER CELL, v.39, no.8, pp.1099 - 1114+e8
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER CELL
- Volume
- 39
- Number
- 8
- Start Page
- 1099
- End Page
- 1114+e8
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/141325
- DOI
- 10.1016/j.ccell.2021.06.001
- ISSN
- 1535-6108
- Abstract
- Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3(E928G) kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3K alpha inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.
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