DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer

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 re-growth. 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 ther

SUBMITTER: Majid Momeny 

PROVIDER: S-SCDT-10_1038-S44321-024-00088-0 | biostudies-other |

REPOSITORIES: biostudies-other