A STATement on Vemurafenib-Resistant Melanoma

Despite recent advancements in the treatment of late-stage mutant BRAF V600E/K melanomas, a major hurdle continues to be acquired resistance to BRAF inhibitors such as Vemurafenib. The mechanisms for resistance have proven to be heterogeneous, emphasizing the need to utilize broad therapeutic approachs. The present study, “Stat3 targeted therapies overcome the acquired resistance to vemurafenib in melanomas ” by Liu et al., proposes that STAT3-PAX3 signaling may be a mechanism that is utilized by melanomas to resist RAF inhibitors. Mutations in the serine/threonine kinase BRAF are found in 45–50 % of melanomas. The development of clinical inhibitors to steps in the BRAF-MEK-ERK1/2 pathway have led to FDA-approval of the RAF inhibitor vemurafenib in late-stage mutant BRAF V600E/K melanomas. However, the initial clinical responses to vemurafenib are heterogeneous, with median progression-free survival of only 6–7 months. Almost all patients who experience an initial response ultimately acquire resistance that allows disease progression, emphasizing the need to identify and target mechanisms of resistance both to vemurafenib and to other RAF inhibitors. Several mechanisms employed by mutant BRAF melanoma cells to overcome RAF inhibition have been described previously (Aplin et al., 2011). Most of thes