Targeting kinome reprogramming in ESR1 fusion-driven breast cancer

摘要: Background: Transcriptionally active ESR1 gene fusions (ESR1-TAF) are a potent cause of estrogen receptor alpha-positive (ERα+) breast cancer endocrine therapy (ET) resistance. These ESR1-TAF are gain-of-function mutations, exhibiting estrogen-independent cell growth, motility and ET resistance. They are not directly druggable because the ERα C-terminal ligand binding domain (LBD) encoding sequence is replaced with a translocated in-frame partner gene sequence. Herein we utilized proteomic approaches to develop novel targeted therapies against ESR1-TAF driven tumorigenesis. Methods: ESR1 fusion cDNA constructs were expressed in ERα+ breast cancer cell lines (T47D and MCF7). Cell growth was assayed by an Alamar blue assay. A mass spectrometry (MS)-based Kinase Inhibitor Pulldown Assay (KIPA) was employed to identify druggable kinases that are commonly upregulated by diverse …