The interplay between inhibition of JAK2 and HSP90

Abstract

A recent article by Weigert et al. published in The Journal of Experimental Medicine described the in vitro generation of synthetic mutations in Janus kinase 2 (JAK 2) that decreased the potency of JAK2 (or JAK1/JAK2) inhibitors in artificial systems. The authors found that heat shock protein 90 (HSP90) inhibitors circumvented the potency shift and suggested that HSP90 inhibition may abrogate JAK inhibitor resistance in these experimental systems. However, the clinical relevance of these laboratory-generated JAK2 mutations, which have not been identified to-date in patients treated with JAK inhibitors, and the therapeutic potential of HSP90 inhibitors in diseases involving aberrant JAK-STAT signaling remain to be determined.

Keywords: HSP90; JAK inhibitor; Janus kinase; mutation; resistance.

Figure 1. A model based on the findings of the study by Weigert et al. would imply that in the presence of certain JAK2 mutations, JAK2 inhibitors may be unable to maximally inhibit JAK-STAT signaling (A). In this model, the co-administration of an HSP90 inhibitor could supplement the effect of a JAK2 inhibitor to overcome compromised JAK2 inhibitor potency (B).