Self-inhibition of HER2 and HER3 at fever temperatures may prevent their hetero-dimerization.

HER2 and HER3 receptors dimerize into potent pro-oncogenic complexes involved in various aggressive and recurrent tumors. The role of febrile temperatures on the formation of HER2:HER3 complexes is unknown. To this end, molecular dynamics simulations of HER2 and HER3 were performed in the 37 °C-40 °C range. HER2 and ligand-free HER32 display inactive conformers that cannot form complexes at 40 °C, while maintaining their extended conformations able to dimerize in the 37 °C-39 °C range. Thermal therapy at particular fever points may complement existing therapy options for HER2-relevant cancers.Communicated by Ramaswamy H. Sarma.