Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 15, 2020
- Source ID
- 10.1158/0008-5472.can-20-0435
Entities
People
- Andrew Goodspeed
- Angelo D'Alessandro
- Daniel L. Gustafson
- Daniel P Regan
- Deguang Kong
- Dominique Ramirez
- Elena Barnaeva
- Heide L Ford
- Hengbo Zhou
- James Costello
- Jennyvette Trinidad-pineiro
- Jessica Y Hsu
- Juan Marugan
- Lesley Mathews Griner
- Lingdi Zhang
- Marc Ferrer
- Matthew D Galbraith
- Melanie A. Blevins
- Michael U.j. Oliphant
- Noel Southall
- Rachel Culp-hill
- Rebecca King
- Rui Zhao
- Samarjit Patnaik
- Xin Hu
Organizations
- American Association for Cancer Research
- Colorado State University
- National Institutes of Health
- United States Department of Defense
- University of Colorado