Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer

Preclinical models of breast cancer that better predict patient-specific drug responses are critical for expanding the clinical utility of targeted therapies, including for inhibitors of poly(ADP-ribose) polymerase (PARP). Reprogramming primary cancer cells into human induced pluripotent stem cells (hiPSCs) recently emerged as a powerful tool to model drug response phenotypes, but its use to date has been limited to hematopoietic malignancies. We designed an optimized reprogramming methodology to generate breast cancer-derived hiPSCs (BC-hiPSCs) from nine patients representing all major subtypes of breast cancer. BC-hiPSCs retain patient-specific oncogenic variants, including variants unique to individual tumor subclones. Additionally, we developed a protocol to differentiate BC-hiPSCs into mammary epithelial cells and mammary-like organoids for in vitro disease modeling, including drug response phenotyping. Using these tools, we demonstrated that BC-hiPSCs can be used to screen for differential sensitivity to PARP inhibitors and mechanistically investigated the causal genetic variant driving drug sensitivity in one patient. Comparative gene expression profiling analysis of RNA-seq data for primary breast cancer derived mammary epithelial cells (MEC), undifferentiated hiPSCs, and hiPSCs differentiated into mammary epithelial cells (hiPSC-MEC), endothelial cells (hiPSC-EC), or cardiomyocytes (hiPSC-CM). Three to five biological replicates (independent cell lines) provided for each cell type.