A novel screen for druggable targets that drive formation and maintenance of breast cancer stem cells

Project: A novel screen for druggable targets that drive formation and maintenance of breast cancer stem cells

Principal Investigator - Rosemary Akhurst

ABSTRACT

TGF-β signaling is implicated in formation and maintenance of a cancer stem cell-like (CSC) phenotype that plays a central role in driving tumor metastasis, recurrence and drug resistance. We demonstrated that down-stream TGFβ signaling might be activated independently of the TGFβ receptors[1]. The hypothesis to be tested is that kinases other than TGFβRII, TGFβR1, ACVR1b and ACVR1c can phosphorylate and activate canonical targets of the proximal TGFβ signaling pathway, Smad2 and Smad3, to independently drive carcinoma cells towards the CSC phenotype.

Translational potential: Identification of druggable kinases that would target the breast CSC.

The specific aims of the current project are:

1. To screen the NCI-50 breast cancer panel for quantitative P-Smad2/3 responses to TGF-β and the TβRI kinase inhibitor Ly2109761, in order to select cell lines for use in the kinase screen of Aim 2.
2. To screen for kinases that can activate P-Smad2/3 independently of TGFβR1 thus conferring resistance to Ly2109761, a TβRI inhibitor.
3. Examination of innate expression levels of the(se) Smad activating kinase(s) in panels of human primary breast carcinoma by tissue microarray and IHC.

Significance: This project may provide new insights into the molecular regulation of CSC maintenance by TGF-β and might provide novel druggable targets for attacking CSCs.