2. Academic Validation
  3. Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis

Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis

  • Cancer Res. 2020 Jun 15;80(12):2689-2702. doi: 10.1158/0008-5472.CAN-20-0435.
Hengbo Zhou 1 2,  Melanie A Blevins 3,  Jessica Y Hsu 1,  Deguang Kong 1,  Matthew D Galbraith 1,  Andrew Goodspeed 1 4,  Rachel Culp-Hill 3,  Michael U J Oliphant 1,  Dominique Ramirez 5,  Lingdi Zhang 3,  Jennyvette Trinidad-Pineiro 3,  Lesley Mathews Griner 6,  Rebecca King 6,  Elena Barnaeva 6,  Xin Hu 6,  Noel T Southall 6,  Marc Ferrer 6,  Daniel L Gustafson 4 5,  Daniel P Regan 4 5,  Angelo D'Alessandro 3 4,  James C Costello 1 4,  Samarjit Patnaik 6,  Juan Marugan 6,  Rui Zhao 7 4,  Heide L Ford 8 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 2 Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 3 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 4 University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 5 Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado.
  • 6 Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland.
  • 7 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. heide.ford@cuanschutz.edu Rui.Zhao@cuanschutz.edu.
  • 8 Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. heide.ford@cuanschutz.edu Rui.Zhao@cuanschutz.edu.
PMID: 32341035 DOI: 10.1158/0008-5472.CAN-20-0435
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.

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