TRK inhibitors, like essentially all targeted therapies, are vulnerable to resistance mutations, and several resistance mutations to Vitrakvi and the recently approved Rozlytrek have been described. The most common form of resistance to targeted therapies, and the only mechanisms that have been described for TRK inhibitors to date, are due to mutations in the target itself. Now, researchers at Memorial Sloan-Kettering Cancer Center have described resistance to TRK inhibitors that occurred due to activation of the MAP kinase (MAPK) pathway.