A1 Refereed original research article in a scientific journal
DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer
Authors: Momeny, Majid; Tienhaara, Mari; Sharma, Mukund; Chakroborty, Deepankar; Varjus, Roosa; Takala, Iina; Merisaari, Joni; Padzik, Artur; Vogt, Andreas; Paatero, Ilkka; Elenius, Klaus; Laajala, Teemu D; Kurppa, Kari J; Westermarck, Jukka
Publisher: Wiley-Blackwell
Publication year: 2024
Journal: EMBO Molecular Medicine
Journal name in source: EMBO molecular medicine
Journal acronym: EMBO Mol Med
Volume: 16
Issue: 7
First page : 1603
Last page: 1629
ISSN: 1757-4676
eISSN: 1757-4684
DOI: https://doi.org/10.1038/s44321-024-00088-0
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/456991133
Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.
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Funding information in the publication:
This study was supported by funding from Finnish Cancer Associations (JW), Foundation of Finnish Cancer Institute (MM), Maud Kuistila Foundation (MM), Turku University Foundation (MM), Finnish Cancer Institute (TDL), Finnish Cultural Foundation (TDL), and Finnish Cultural Foundation (KJK).
