Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells

Abstract

// Alastair H. Davies 1 , Kristen Reipas 2 , Kaiji Hu 3 , Rachel Berns 3 , Natalie Firmino 3 , Anna L. Stratford 3 and Sandra E. Dunn 4 1 Department of Urological Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada 2 School of Medicine, Queen’s University, Kingston, ON, Canada 3 Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada 4 Phoenix Molecular Diagnostics, Richmond, BC, Canada Correspondence to: Sandra E. Dunn, email: // Keywords : RSK, YB-1, drug resistance, drug target, cancer stem cells, breast cancer Received : April 20, 2015 Accepted : April 23, 2015 Published : May 14, 2015 Abstract The triple-negative breast cancer (TNBC) subtype is enriched in cancer stem cells (CSCs) and clinically correlated with the highest rate of recurrence. Several studies implicate the RSK pathway as being pivotal for the growth and proliferation of CSCs, which are postulated to drive tumor relapse. We now address the potential for the newly developed RSK inhibitor LJI308 to target the CSC population and repress TNBC growth and dissemination. Overexpression of the Y-box binding protein-1 (YB-1) oncogene in human mammary epithelial cells (HMECs) drove TNBC tumor formation characterized by a multi-drug resistance phenotype, yet these cells were sensitive to LJI308 in addition to the classic RSK inhibitors BI-D1870 and luteolin. Notably, LJI308 specifically targeted transformed cells as it had little effect on the non-tumorigenic parental HMECs. Loss of cell growth, both in 2D and 3D culture, was attributed to LJI308-induced apoptosis. We discovered CD44+/CD49f+ TNBC cells to be less sensitive to chemotherapy compared to the isogenic CD44-/CD49f- cells. However, inhibition of RSK using LJI308, BI-D1870, or luteolin was sufficient to eradicate the CSC population. We conclude that targeting RSK using specific and potent inhibitors, such as LJI308, delivers the promise of inhibiting the growth of TNBC.