Abstract PR07: A systems biology approach to reprogramming drug-resistant breast cancer stem-like cells

Breast cancer stem-like cells (CSCs) are hypothesized to be a cause of poor outcome in patients, and are drug-resistant in vitro and in PDX mice. We performed plate-based single-cell RNA sequencing (scRNA-seq) on flow sorted fresh tumor samples. These data were analyzed using our metaVIPER algorithm, which infers protein activity in a manner that is robust to the effects of noise and gene dropout. metaVIPER identified known breast CSC regulators, and analysis with our OncoTreat algorithm predicted several FDA approved drugs that could reprogram the breast CSCs into a state resembling that of differentiated tumor cells. We tested two of these predictions, ivermectin and albendazole, in TNBC PDX mice, and performed scRNA-seq on fresh tumor samples after 14 days of treatment. The results were exciting, as measured by single-cell entropy or lineage marker analysis. Breast CSCs were reprogrammed as predicted, while a tumor treated with a traditional chemotherapeutic (paclitaxel) had a dramatically higher proportion of CSCs. These results suggested a therapy in which cells are cyclically reprogrammed and treated with a conventional cytotoxic drug. This reprogram-kill-repeat therapy is being tested in TNBC PDX mice. We believe that the strategy developed here will prove to be a powerful tool for understanding and manipulating cell-state in heterogeneous populations. Citation Format: Jeremy Worley, Hongxu Ding, Heeju Noh, Evan Paull, Erin Bush, Piero Dalerba, Peter Sims, Fil Dela Cruz, Andrew Kung, Andrea Califano. A systems biology approach to reprogramming drug-resistant breast cancer stem-like cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR07.