A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance

• Published in: Oncogene Vol. 40; no. 7; pp. 1300 - 1317
• Main Authors: Al-Akhrass, Hussein, Conway, James R. W., Poulsen, Annemarie Svane Aavild, Paatero, Ilkka, Kaivola, Jasmin, Padzik, Artur, Andersen, Olav M., Ivaska, Johanna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.02.2021; Nature Publishing Group
• Subjects: 13/95; 14/19; 631/67/1347; 631/80/86/2368; 64/116; 82/103; 96/109; 96/35; Animals; Apoptosis; Brain - drug effects; Brain - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell proliferation; Cell Proliferation - drug effects; Cell surface; Development and progression; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epidermal growth factor; ErbB-2 protein; Female; Gene expression; Genetic aspects; Health aspects; Heregulin; Heterografts; Human Genetics; Humans; Internal Medicine; Kinases; LDL-Receptor Related Proteins - genetics; Lysosomes; MAP kinase; Medicine; Medicine & Public Health; Membrane Transport Proteins - genetics; Metastases; Mice; Neuregulin-1 - pharmacology; Oncology; Protein-tyrosine kinase; Protein-tyrosine kinase receptors; rab4 GTP-Binding Proteins - genetics; Receptor, ErbB-2 - genetics; Receptor, ErbB-3 - genetics; Spheroids; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Transcription; Xenografts; Zebrafish; Finland
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01604-5

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.