A Triazine Compound S06 Inhibits Proinvasive Crosstalk between Carcinoma Cells and Stromal Fibroblasts via Binding to Heat Shock Protein 90

SummaryCarcinoma-associated fibroblasts (CAFs) promote tumor invasion by secreting soluble factors. A tagged triazine library was screened in our novel transwell coculture model of CAF and oral squamous cell carcinoma (OSCC). We discovered compound S06, which reduced OSCC invasion by inhibiting secretion of CAF-derived proinvasive chemokines. The N-terminus of Hsp90 was found to be the cellular target of S06. Importantly, S06 did not induce hepatic toxicity, a side effect associated with well-known Hsp90 inhibitors. Moreover, S06 inhibited tumor cell migration in a zebrafish xenograft model. Our results demonstrate that Hsp90 is a novel target for stromal-based therapy to modulate proinvasive molecular crosstalk within the tumor microenvironment. Furthermore, S06 represents a new class of Hsp90 inhibitor and is an attractive candidate for anticancer drug development.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (201 K)Download as PowerPoint slideHighlights► A screening system was developed for finding inhibitors of tumor-stroma crosstalk ► Novel triazine S06 inhibits cancer invasion by blocking tumor-stroma crosstalk ► Hsp90 was found as a molecular target of S06 using affinity chromatography