Structural mechanism of inhibitor-resistance by ERK2 mutations

Abstract

Extracellular signal-regulated kinase (ERK) is a serine-threonine kinase that is involved in the regulation of cellular signals. ERK inhibitors have been developed to treat cancers with B-Raf proto-oncogene mutations. However, the use of these inhibitors in disease settings induces ERK mutations resistant to the inhibitors, which poses major difficulties in effective cancer treatment. Here, we present the crystal structures of the ERK Y36H and G37C mutants that occur in cancer cells resistant to ERK inhibitors. The structures revealed mechanisms by which these mutations confer inhibitor-resistance to ERK. The Y36H mutant structure revealed a resistance mechanism that involves rotations of the His36 residue in the Gly-rich loop and the Tyr64 residue in the helix C, which blocks the entrance of inhibitors to the ATP-binding pocket. Furthermore, the G37C mutant structure exhibited that the mutation-induced rigidity in dihedral angles plays a major role in inducing inhibitor-resistance. Detailed structural information on the resistance mechanism suggests strategy for designing of novel inhibitors that can circumvent mutation-induced inhibitor resistance.