CCR Translations Inhibition of Vascular Endothelial Growth Factor Receptor-1/Wnt/ β-catenin Crosstalk Leads to Tumor Cell Death

In this issue of Clinical Cancer Research, Naik and colleagues (1) provide the rationale for a synthetic lethal therapy theoretically based on targeted inhibition of vascular endothelial growth factor receptor-1 (VEGFR1)-mediated kinase activity in Wnt/βcatenin-addicted human colorectal cancer (CRC) cells (Fig. 1). Wnt is a cysteine-rich secreted molecule and prototype of a 19-member family of proteins. It activates target genes primarily through binding and stabilization of the Frizzled/LRP6 membrane receptor complex. This complex sequestrates cytoplasmic Axin thus preventing it from mediating the ubiquitination and degradation of β-catenin. Stable β-catenin is phosphorylated and translocated to the nucleus, where it targets the TCF/LEF family of transcription factors and promotes expression of genes that regulate cell proliferation and cell polarity (2). A significant proportion of CRCs have an activating mutation in the Wnt/β-catenin pathway resulting in the abnormal expression of proliferation mediators and growth factors (e.g., C-myc and VEGF; ref. 3). Naik and colleagues (1) expose a direct link between VEGFR1 function and the Wnt/β-catenin signaling pathway in CRC cells. To determine this linkage, they developed a Wnt/β-catenin screening protocol conceptually based on the phenomenon of synthetic lethality (4). The authors used a series of small inhibitory RNA (siRNA) and short hairpin RNA (shRNA) panels to interrogate a human embryonic kidney cell line (STF293) bearing a Wnt/β-catenin-responsive reporter gene. RNA interference protocols have been introduced recently as synthetic lethal screens and have already begun to uncover other unexpected linkages between genes and survival pathways that show prom-