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

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  • Hussein Al-Akhrass, Åbo Akademi University
  • ,
  • James R.W. Conway, Åbo Akademi University
  • ,
  • Annemarie Svane Aavild Poulsen
  • Ilkka Paatero, Åbo Akademi University
  • ,
  • Jasmin Kaivola, Åbo Akademi University
  • ,
  • Artur Padzik, Åbo Akademi University
  • ,
  • Olav M. Andersen
  • Johanna Ivaska, Åbo Akademi University

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.

Original languageEnglish
JournalOncogene
Volume40
Issue7
Pages (from-to)1300-1317
Number of pages18
ISSN0950-9232
DOIs
Publication statusPublished - 18 Feb 2021

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