Identification and Pharmacological Targeting of Treatment-Resistant, Stem-like Breast Cancer Cells for Combination Therapy

Author:

Worley Jeremy,Noh Heeju,You Daoqi,Turunen Mikko M.,Ding Hongxu,Paull Evan,Griffin Aaron T.,Grunn Adina,Zhang Mingxuan,Guillan Kristina,Bush Erin C.,Brosius Samantha J.,Hibshoosh Hanina,Mundi Prabhjot S.ORCID,Sims Peter,Dalerba Piero,Cruz Filemon S. DelaORCID,Kung Andrew L.,Califano Andrea

Abstract

AbstractTumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential—often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulationin vivowithout noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel—a commonly used chemotherapeutic —displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.

Publisher

Cold Spring Harbor Laboratory

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