SORLA regulates endosomal trafficking and oncogenic fitness of HER2

Mika Pietilä (), Pranshu Sahgal, Emilia Peuhu, Niklas Z. Jäntti, Ilkka Paatero, Elisa Närvä, Hussein Al-Akhrass, Johanna Lilja, Maria Georgiadou, Olav M. Andersen, Artur Padzik, Harri Sihto, Heikki Joensuu, Matias Blomqvist, Irena Saarinen, Peter J. Boström, Pekka Taimen and Johanna Ivaska ()
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Mika Pietilä: University of Turku and Åbo Akademi University
Pranshu Sahgal: University of Turku and Åbo Akademi University
Emilia Peuhu: University of Turku and Åbo Akademi University
Niklas Z. Jäntti: University of Turku and Åbo Akademi University
Ilkka Paatero: University of Turku and Åbo Akademi University
Elisa Närvä: University of Turku and Åbo Akademi University
Hussein Al-Akhrass: University of Turku and Åbo Akademi University
Johanna Lilja: University of Turku and Åbo Akademi University
Maria Georgiadou: University of Turku and Åbo Akademi University
Olav M. Andersen: Aarhus University
Artur Padzik: University of Turku and Åbo Akademi University
Harri Sihto: Helsinki University Hospital
Heikki Joensuu: Helsinki University Hospital
Matias Blomqvist: Turku University Hospital
Irena Saarinen: Turku University Hospital
Peter J. Boström: University of Turku and Turku University Hospital
Pekka Taimen: Turku University Hospital
Johanna Ivaska: University of Turku and Åbo Akademi University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

Date: 2019
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DOI: 10.1038/s41467-019-10275-0

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