A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer
Tekijät: 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
Kustantaja: Wiley-Blackwell
Julkaisuvuosi: 2024
Journal: EMBO Molecular Medicine
Tietokannassa oleva lehden nimi: EMBO molecular medicine
Lehden akronyymi: EMBO Mol Med
Vuosikerta: 16
Numero: 7
Aloitussivu: 1603
Lopetussivu: 1629
ISSN: 1757-4676
eISSN: 1757-4684
DOI: https://doi.org/10.1038/s44321-024-00088-0
Rinnakkaistallenteen osoite: 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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
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).
