Issues

Acquired resistance to kinase inhibitor therapy often involves mutation of the ATP binding site of the targeted protein. However, mutation within Helix A of MEK1, which is distant from the ATP binding pocket, is shown bound to ADP in gray, and the allosteric binding pocket is shown bound to the MEK inhibitor trametinib (yellow), can promote resistance to BRAF inhibitors or trametinib in BRAF mutant melanoma cells. Combinations including the BRAF inhibitor dabrafenib and trametinib can overcome this resistance. The image and model of trametinib bound to MEK1 were created with Maestro (Schrodinger, LLC). For details, see article by Greger and colleagues on page 909.