Abstract B52: Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use
| Autor: | Mariano J. Alvarez, Carl Pelz, Rosalie C. Sears, Joe W. Gray, Tyler Risom, Andrea Califano, Juha Rantala, Katie Johnson-Camacho, Ellen M. Langer, Paul T. Spellman, Nicholas J. Wang |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Molecular Cancer Research. 14:B52-B52 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1557-3125.advbc15-b52 |
| Popis: | The use of small-molecule kinase inhibitors is a promising therapeutic strategy for the management of breast cancer. Positive responses to these agents, however, are often transient, and acquired resistance arises in the course of weeks to months. Recent studies have demonstrated that phenotypic plasticity in cancer cell populations can provide adaptive resistance to small-molecule kinase inhibitors, whereby cancer cells transition to drug-tolerant phenotypic states, reliant on compensatory survival and proliferative signaling pathways. Drug combinations and sequences can prevent this adaptive resistance to targeted therapy, however, nominating effective drug pairs is challenging. In this study, we seek to identify such drug combinations through first identifying single agent therapeutics that reduce phenotypic heterogeneity and enrich distinct cell-states with common pathway reliance. To do so, we focus on phenotypic heterogeneity in tumor-cell lineage-state; using immunofluorescent staining against markers of the luminal, basal, and mesenchymal lineages, we combine high-throughput drug screening with high-content imaging and pursue small-molecule inhibitors that reduce phenotypic heterogeneity and promote the accumulation of particular lineage-states in residual cell populations. We observe pronounced lineage-state heterogeneity in Triple-Negative tumors and Basal-Like breast cancer cell lines, and find that the lineage-state distributions are greatly influenced by numerous therapeutics. MEK and PI3K/mTOR inhibitors in particular induce robust time- and dose-dependent alterations is lineage-state distribution in residual cell populations, selecting for a cell population enriched in, or depleted of a basal lineage-state, respectively. Through gene expression profiling and master-regulator analysis of active transcriptional states in the residual cell populations, we are able to identify compensatory-signaling pathways. We demonstrate that combining MEK and PI3K/mTOR inhibitors with agents targeting these compensatory pathways induces synergistic antiproliferative effects. Citation Format: Tyler Risom, Ellen Langer, Juha Rantala, Mariano Alvarez, Katie Johnson-Camacho, Carl Pelz, Nicholas Wang, Paul Spellman, Andrea Califano, Joe Gray, Rosalie Sears. Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B52. |
| Databáze: | OpenAIRE |
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