Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors
Menée in vitro, cette étude met en évidence des mécanismes par lesquels l'expression de gènes mutés JAK1 et JAK3 favorise l'apparition d'une résistance à un traitement à base d'inhibiteurs de JAK tels que le ruxolitinib ou le CMP6
The acquisition of growth signal self-sufficiency is one of the hallmarks of cancer. We previously reported that the murine IL-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the JAK-STAT pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3 or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation, and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short term assays. However, resistant clones occur upon long term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the ATP-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas, cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T cell transformation, and represent a new mechanism of acquisition of resistance against JAK inhibitors.