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Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis
Hengbo Zhou1,2, Melanie A Blevins3, Jessica Y Hsu1
1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Abstract:
Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis in vivo without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacologic inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis. SIGNIFICANCE: These findings identify and characterize a novel inhibitor of the SIX1/EYA2 complex that reverses EMT phenotypes suppressing breast cancer metastasis.
Insights
A new compound, 8430, inhibits the SIX1/EYA2 complex, a key driver of breast cancer metastasis. This targeted approach suppresses metastasis without affecting primary tumor growth, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Metastasis is the primary cause of cancer mortality, often driven by dysregulated developmental signaling pathways.
- The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) complex is crucial for development and its aberrant expression promotes breast cancer metastasis via TGFβ signaling and epithelial-mesenchymal transition (EMT).
- SIX1 also promotes metastasis through non-cell autonomous mechanisms, including GLI-signaling activation and VEGFC-induced lymphangiogenesis.
Purpose of the Study:
- To identify and characterize novel small molecule inhibitors targeting the SIX1/EYA2 transcriptional complex.
- To evaluate the efficacy of a novel compound, NCGC00378430 (8430), in suppressing breast cancer metastasis.
- To assess the safety and tolerability of 8430 in vivo.
Main Methods:
- Identification of a small molecule compound (8430) that inhibits the SIX1/EYA2 interaction.
- Assessment of 8430's ability to reverse SIX1-mediated transcriptional and metabolic profiles.
- Evaluation of 8430's effect on SIX1-induced TGFβ signaling and EMT.
- In vivo studies in mice to determine the efficacy and tolerability of 8430 in suppressing breast cancer metastasis.
Main Results:
- Compound 8430 was identified, effectively reducing the SIX1/EYA2 interaction.
- 8430 partially reversed SIX1-driven transcriptional and metabolic changes.
- 8430 inhibited SIX1-induced TGFβ signaling and EMT.
- 8430 was well-tolerated in mice and significantly suppressed breast cancer metastasis in vivo without impacting primary tumor growth.
Conclusions:
- Pharmacologic inhibition of the SIX1/EYA2 complex is a viable strategy to suppress breast cancer metastasis.
- Compound 8430 represents a novel therapeutic agent capable of reversing EMT phenotypes and inhibiting metastasis.
- Targeting the SIX1/EYA2 complex offers a promising approach for treating metastatic breast cancer with potentially limited side effects.
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