Abstract A070: Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer

Abstract

Abstract Patient-derived human induced pluripotent stem cells (hiPSCs) are a powerful tool for disease modeling because hiPSCs provide a scalable source of cells that retain patient-specific genomic variants. Recently, somatic cell reprogramming has been applied to modeling cancer: cancer cells are reprogrammed into hiPSCs, then re-differentiated into the relevant cancer cell lineage. hiPSCs derived from cancer cells retain tumor- and subclone-specific genomic variants and drug sensitivities, providing a unique tool to deconstruct the contributions of tumor heterogeneity to drug response. While hiPSCs have been shown to model various hematological malignancies, no study to date has examined the potential of hiPSCs to model breast cancer. We demonstrate for the first time that primary human breast cancer cells can be reprogrammed into hiPSCs by transiently overexpressing canonical reprogramming factors. Using an optimized reprogramming methodology, we generated a biobank of >200 hiPSC lines from 10 breast tumor samples, including hormone receptor positive, HER2 positive, and triple negative breast tumors. Breast tumor-derived hiPSCs retain patient-specific oncogenic variants. Additionally, we present a protocol to differentiate hiPSCs into mammary epithelial cells (hiPSC-MECs) and mammary-like organoids for in vitro disease modeling. hiPSC-MECs are proliferative and exhibit a gene expression profile that closely resembles primary MECs. Finally, we demonstrate that this breast tumor model can be used to assess patient-specific responses to PARP inhibitors. We show that hiPSC-MECs derived from BRCA1 and BRCA2 mutant tumors are deficient in homology-directed repair and are more sensitive to PARP inhibitor treatment. This work establishes the foundation of hiPSCs as a novel disease modeling platform for breast cancer and highlights the potential of tumor-derived hiPSCs to predict patient and subclone-specific drug responses. Citation Format: Carly Weddle, Paul Burridge. Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A070.