期刊
ONCOGENE
卷 40, 期 7, 页码 1300-1317出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-01604-5
关键词
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资金
- Academy of Finland [312517]
- Academy of Finland CoE for Translational Cancer Biology
- European Research Council CoG grant [615258]
- Sigrid Juselius Foundation
- Finnish Cancer Organization
- Finnish Cultural Foundation Central Fund [190150]
- European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant [841973]
- Independent Research Fund Denmark [DFF-4004-00371]
- TuDMM Doctoral Program, University of Turku
- Marie Curie Actions (MSCA) [841973] Funding Source: Marie Curie Actions (MSCA)
- European Research Council (ERC) [615258] Funding Source: European Research Council (ERC)
- Academy of Finland (AKA) [312517, 312517] Funding Source: Academy of Finland (AKA)
Resistance to HER2-targeted therapies in breast cancer is often associated with HER3 signaling, and the interaction between SorLA and HER3 has been found to play a key role in regulating the stability of the HER2-HER3 dimer. Loss of SorLA compromises heregulin-induced cell proliferation and sensitizes metastatic anti-HER2 therapy-resistant cells to neratinib, indicating a potential therapeutic target for overcoming resistance mechanisms.
Current evidence indicates that resistance to the tyrosine kinase-type cell surface receptor (HER2)-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer is essential to decipher therapy relapse mechanisms. Here, we investigate a bidirectional relationship between HER2-HER3 signaling and a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1). We demonstrate that heregulin-mediated signaling supports SorLA transcription downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer in a Ras-related protein Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model.
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