DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer
Majid Momeny1,2, Mari Tienhaara3,4, Mukund Sharma5,4
1Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland. majid.momeny@uth.tmc.edu.
Abstract:
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.
Insights
Dual-specificity phosphatase DUSP6 drives cancer cell regrowth under HER2-targeted therapy. Targeting DUSP6 overcomes resistance by blocking the neuregulin-HER3 pathway, offering a new strategy for HER2+ breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial in cancer therapy, but tumor resistance limits their efficacy.
- HER2-positive (HER2+) breast cancers often develop resistance to HER2 inhibitors (HER2i), leading to tumor regrowth.
- Understanding resistance mechanisms is vital for improving TKI-based cancer treatments.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to HER2 inhibitors in HER2+ breast cancer.
- To identify novel therapeutic targets that can overcome TKI resistance.
- To explore the role of phosphatases in drug tolerance and tumor relapse.
Main Methods:
- Transcriptional profiling of HER2+ breast cancer cells under continuous HER2 inhibitor therapy.
- Analysis of dual-specificity phosphatase DUSP6 expression in dormant and re-proliferating cells.
- Functional studies involving DUSP6 overexpression and pharmacological inhibition.
- Investigation of the neuregulin-HER3 signaling axis.
- In vivo studies using a brain metastasis model.
Main Results:
- DUSP6 expression was inhibited in dormant cells and strongly induced upon regrowth, correlating with poor patient survival.
- DUSP6 overexpression conferred apoptosis resistance, while its blockade prevented therapy tolerance.
- DUSP6 positively regulates HER3 expression, mediating resistance through the neuregulin-HER3 axis.
- Pharmacological targeting of DUSP6 synergized with HER2 inhibitors and demonstrated synthetic lethality in vivo.
Conclusions:
- DUSP6 is a key driver of escape from HER2 inhibitor-induced dormancy in HER2+ breast cancer.
- DUSP6 is a druggable target that can overcome HER3-driven TKI resistance.
- Targeting DUSP6 offers a promising strategy to enhance the efficacy of HER2 inhibitors and combat cancer recurrence.
