Proteogenomic Approaches for Finding Therapeutic Vulnerabilities in Metastatic Breast Tumors Expressing Transcriptionally Active ESR1 Fusions
Abstract
Estrogen receptor- positive (ER+) breast cancer is often initially responsive to endocrine therapy (ET), but many patients succumb to metastatic ET-resistant disease. This project focuses on drivers of ET resistance in the form of transcriptionally active, in-frame ESR1gene fusions, which encode chimeric proteins completely refractory to all ET due to the lack of the ligand binding domain of ESR1. The hypothesis tested is that active, but not inactive,ESR1 fusions identified in metastatic patients induce ET resistance and metastasis by predictable reprogramming of gene expression (Aim 1), of protein kinase expression (Aim 2),and by recruitment of a common set of coactivators (Aim 3). We have made great strides in this first year period for Aims 1 and 2, and begun experiments for Aim 3. Briefly, in Aim 1,we have established functional rules that predict which ESR1 fusions are active drivers by identifying a 24-gene expression signature that active ESR1 fusions promote. In Aim 2, we have discovered that the RET receptor tyrosine kinase has elevated expression when activeESR1 fusions are expressed in breast cancer cells and that an inhibitor of RET reduces the growth of these cells, both in vitro and in patient-derived xenograft (PDX) tumors in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2022
- Accession Number
- AD1174416
Entities
People
- Charles E Foulds
- Matthew J Ellis
Organizations
- Baylor College of Medicine