Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple negative breast cancer

Citation

Kwon Y, Petrie K, Leibovitch B, Zeng L, Mezei M, Howell L, Gil V, Christova R, Bansal N, Yang S, Sharma R, Ariztia EV, Frankum J, Brough R & Sbirkov Y (2015) Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple negative breast cancer. Molecular Cancer Therapeutics, 14 (8), pp. 1824-1836. https://doi.org/10.1158/1535-7163.MCT-14-0980-T

Abstract
Triple-negative breast cancers (TNBC) lacking estrogen, progesterone, and HER2 receptors account for 10% to 20% of breast cancer and are indicative of poor prognosis. The development of effective treatment strategies therefore represents a pressing unmet clinical need. We previously identified a molecularly targeted approach to target aberrant epigenetics of TNBC using a peptide corresponding to the SIN3 interaction domain (SID) of MAD. SID peptide selectively blocked binding of SID-containing proteins to the paired α-helix (PAH2) domain of SIN3, resulting in epigenetic and transcriptional modulation of genes associated with epithelial–mesenchymal transition (EMT). To find small molecule inhibitor (SMI) mimetics of SID peptide, we performed anin silicoscreen for PAH2 domain–binding compounds. This led to the identification of the avermectin macrocyclic lactone derivatives selamectin and ivermectin (Mectizan) as candidate compounds. Both selamectin and ivermectin phenocopied the effects of SID peptide to block SIN3–PAH2 interaction with MAD, induce expression ofCDH1andESR1, and restore tamoxifen sensitivity in MDA-MB-231 human and MMTV-Myc mouse TNBC cellsin vitro. Treatment with selamectin or ivermectin led to transcriptional modulation of genes associated with EMT and maintenance of a cancer stem cell phenotype in TNBC cells. This resulted in impairment of clonogenic self-renewalin vitroand inhibition of tumor growth and metastasisin vivo. Underlining the potential of avermectins in TNBC, pathway analysis revealed that selamectin also modulated the expression of therapeutically targetable genes. Consistent with this, an unbiased drug screen in TNBC cells identified selamectin-induced sensitization to a number of drugs, including those targeting modulated genes.

Notes
Additional co-authors: Alan Ashworth, Christopher J. Lord, Arthur Zelent, Eduardo Farias, Ming-Ming Zhou, and Samuel Waxman

Journal
Molecular Cancer Therapeutics: Volume 14, Issue 8