PUBLICATION
A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance
- Authors
- Al-Akhrass, H., Conway, J.R.W., Poulsen, A.S.A., Paatero, I., Kaivola, J., Padzik, A., Andersen, O.M., Ivaska, J.
- ID
- ZDB-PUB-210110-7
- Date
- 2021
- Source
- Oncogene 40(7): 1300-1317 (Journal)
- Registered Authors
- Ivaska, Johanna, Paatero, Ilkka
- Keywords
- none
- MeSH Terms
-
- Animals
- Brain/drug effects
- Brain/metabolism
- Breast Neoplasms/genetics*
- Breast Neoplasms/pathology
- Cell Proliferation/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Female
- Heterografts
- Humans
- LDL-Receptor Related Proteins/genetics*
- Membrane Transport Proteins/genetics*
- Mice
- Neuregulin-1/pharmacology
- Receptor, ErbB-2/genetics*
- Receptor, ErbB-3/genetics*
- Spheroids, Cellular/drug effects
- Spheroids, Cellular/metabolism
- Zebrafish
- rab4 GTP-Binding Proteins/genetics
- PubMed
- 33420373 Full text @ Oncogene
Citation
Al-Akhrass, H., Conway, J.R.W., Poulsen, A.S.A., Paatero, I., Kaivola, J., Padzik, A., Andersen, O.M., Ivaska, J. (2021) A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance. Oncogene. 40(7):1300-1317.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping