Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias
Menée sur des lignées cellulaires de leucémie lymphoblastique aiguë avec mutations du gène JAK, cette étude met en évidence des mécanismes suggérant l'intérêt d'un inhibiteur de la protéine de choc thermique HSP90 pour surmonter une résistance au ruxolitinib
PU-H71, a novel purine scaffold inhibitor, shows potent therapeutic efficacy in JAK-mutant ALL cells and mouse models. HSP90 inhibition retains therapeutic efficacy in ruxolitinib-persistent JAK-mutant ALL cells. The development of the dual JAK1/2 inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathologic responses in MPNs suggests a need for development of better therapies for JAK kinase dependent malignancies. Here we demonstrate that Heat shock protein 90 (HSP90) inhibition utilizing a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells.
Blood 2015