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

Abstract

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.