High Content Phenotypic Screening Identifies Serotonin Receptor Modulators with Selective Activity upon Breast Cancer Cell Cycle and Cytokine Signaling Pathways

Heterogeneity in disease mechanisms between genetically distinct patients
contributes to high attrition rates in late stage clinical drug development. New
personalized medicine strategies aim to identify predictive biomarkers which
stratify patients most likely to respond to a particular therapy. However, for
complex multifactorial diseases not characterized by a single genetic driver,
empirical approaches to identifying predictive biomarkers and the most
promising therapies for personalized medicine are required. In vitro
pharmacogenomics seeks to correlate in vitro drug sensitivity testing across
panels of genetically distinct cell models with genomic, gene expression or
proteomic data to identify predictive biomarkers of drug response. However, the
vast majority of in vitro pharmacogenomic studies performed to date are limited
to dose-response screening upon a single viability assay endpoint. In this article
we describe the application of multiparametric high content phenotypic screening
and the theta comparative cell scoring method to quantify and rank compound
hits, screened at single concentration, which induce a broad variety of divergent
phenotypic responses between distinct breast cancer cell lines. High content
screening followed by transcriptomic pathway analysis identified serotonin
receptor modulators which display selective activity upon breast cancer cell cycle
and cytokine signaling pathways correlating with inhibition of cell growth and
survival. These methods describe a new evidence-led approach to rapidly identify
compounds which display distinct response between different cell types. The
results presented also warrant further investigation of the selective activity of
serotonin receptor modulators upon breast cancer cell growth and survival as a
potential drug repurposing opportunity.