Research ArticleCancer

Wnt/β-Catenin Signaling and AXIN1 Regulate Apoptosis Triggered by Inhibition of the Mutant Kinase BRAFV600E in Human Melanoma

Sci. Signal.  10 Jan 2012:
Vol. 5, Issue 206, pp. ra3
DOI: 10.1126/scisignal.2002274

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Death to Melanoma

Melanoma is a particularly aggressive form of skin cancer. Although the identification of a specific mutation in the kinase-encoding gene BRAF has facilitated the development of clinical therapies, many melanoma patients with the BRAFV600E mutation fail to exhibit long-term responsiveness to inhibition of this kinase. Biechele et al. found that some melanoma cell lines exhibited an enhanced apoptotic response when BRAFV600E was inhibited simultaneously with activation of the Wnt/β-catenin pathway. The susceptibility to this cell death response correlated with the ability of the combination treatment to reduce the abundance of AXIN1, a negative regulator of the Wnt/β-catenin pathway, and knockdown of AXIN1 abundance caused apoptosis-resistant melanoma cell lines to become susceptible to apoptosis in response to the combined treatment. Thus, exploiting this functional crosstalk between BRAF and Wnt/β-catenin signaling may yield more effective therapies for treating melanoma.