Elucidating and Pharmacologically Targeting Master Regulators of Stem-like Breast Cancer Cell State

In many tumors, small subpopulations of stem-like cells can exist in drug-resistant states that are transient and epigenetically governed. Single-cell RNA sequencing provides transcriptional profiles for individual cells which, although sparse and noisy, may provide insight into how they are regulated and how they may be targeted. We took a systems-biology approach to analyzing stem-like cells in breast tumors and predicting how this drug-resistant subpopulation might be sensitized to treatment. Our analysis predicted that the anthelmintic albendazole would reprogram the stem-like population, and a subsequent sensitizing-then-kill experiment in triple negative breast cancer PDX mice revealed a synergistic relationship between albendazole and the first-line treatment, paclitaxel. These results are a proof of concept that it is possible to use, a systems biology approach to identify drugs that can reprogram cell-state, and that tumor subpopulations which have long been considered intractable may be forced into a sensitive state. Overall design: Patient-derived xenograft (PDX) models were generated using dissociated tumor cells obtained from a patient with triple-negative breast carcinoma. The mice (n=2/arm) were treated with paclitaxel, ivermectin, albendazole, and DMSO (control) for 15 days, and tumors were harvested 2 hours after administration of the last dose of vehicle or drug. Then, the prepared libraries using Human Tumor Dissociation Kit (Miltenyi) were sequenced on an Illumina Novaseq 6000.