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

The functional crosstalk between Wnt/β-catenin and BRAF signaling may yield more effective therapies for treating melanoma. 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. Because the Wnt/β-catenin signaling pathway is linked to melanoma pathogenesis and to patient survival, we conducted a kinome small interfering RNA (siRNA) screen in melanoma cells to expand our understanding of the kinases that regulate this pathway. We found that BRAF signaling, which is constitutively activated in many melanomas by the BRAFV600E mutation, inhibits Wnt/β-catenin signaling in human melanoma cells. Because inhibitors of BRAFV600E show promise in ongoing clinical trials, we investigated whether altering Wnt/β-catenin signaling might enhance the efficacy of the BRAFV600E inhibitor PLX4720. We found that endogenous β-catenin was required for PLX4720-induced apoptosis of melanoma cells and that activation of Wnt/β-catenin signaling synergized with PLX4720 to decrease tumor growth in vivo and to increase apoptosis in vitro. This synergistic enhancement of apoptosis correlated with reduced abundance of an endogenous negative regulator of β-catenin, AXIN1. In support of the hypothesis that AXIN1 is a mediator rather than a marker of apoptosis, siRNA directed against AXIN1 rendered resistant melanoma cell lines susceptible to apoptosis in response to treatment with a BRAFV600E inhibitor. Thus, Wnt/β-catenin signaling and AXIN1 may regulate the efficacy of inhibitors of BRAFV600E, suggesting that manipulation of the Wnt/β-catenin pathway could be combined with BRAF inhibitors to treat melanoma.