| Autor: |
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 |
| Zdroj: |
EMBO Molecular Medicine; Jul2024, Vol. 16 Issue 7, p1603-1629, 27p |
| Abstrakt: |
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. Synopsis: Resistance to HER2 inhibitors (HER2i) is common in patients with HER2+ breast cancer and the HER3 signaling pathway is an important mediator of this therapy resistance. This study reveals oncogenic phosphatase DUSP6 as a critical mediator of development of HER2i tolerance via regulation of HER3. DUSP6 has key roles in the emergence of HER2+ drug-tolerant expanding persister (DTEP) cells and in resistance to HER2i therapies. DUSP6 inhibits HER2i-induced apoptosis, and its blockade increases therapeutic sensitivity in vitro and in vivo. DUSP6 determines sensitivity to HER2-directed therapies via regulation of HER3 receptor whereas NRG-activated HER3 drives DUSP6 expression. DUSP6 is a promising small molecule inhibitor target protein for patients with HER2i resistant tumors or HER2+ brain metastasis. Resistance to HER2 inhibitors (HER2i) is common in patients with HER2+ breast cancer and the HER3 signaling pathway is an important mediator of this therapy resistance. This study reveals oncogenic phosphatase DUSP6 as a critical mediator of development of HER2i tolerance via regulation of HER3. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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