In a study reported in the Journal of the National Cancer Institute, Aydin and colleagues found that mutation in and inactivation of FBXW7 and accumulation of NOTCH1, a substrate of FBXW7, were associated with melanoma tumorigenesis.
FBXW7 was found to be mutated in 8% of 103 melanoma patients, and protein expression analysis in 96 human tissue samples and 20 melanoma cell lines showed that FBXW7 inactivation was a common event (40% of cell lines). FBXW7 loss was associated with accumulation of NOTCH1 and other substrates.
Tumor formation in vivo was increased 2.4-fold with ectopic expression of mutant forms of FBXW7 and 3.9-fold with silencing of FBXW7 in immortalized melanocytes. Inactivation of FBXW7 resulted in NOTCH1 activation, a 2.6-fold upregulation of NOTCH1 target genes, and increased tumor angiogenesis. NOTCH1 inhibition resulted in a 5-fold increase in tumor shrinkage.
The investigators concluded, “Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.” ■