Abstract B52: Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use

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 ...

Source: Molecular Cancer Research - February 29, 2016 Category: Cancer & Oncology Authors: Risom, T., Langer, E., Rantala, J., Alvarez, M., Johnson-Camacho, K., Pelz, C., Wang, N., Spellman, P., Califano, A., Gray, J., Sears, R. Tags: Tumor Heterogeneity (Intratumor and Intertumoral): Poster Presentations - Proffered Abstracts Source Type: research