Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias

• Published in: Blood Vol. 126; no. 22; pp. 2479 - 2483
• Main Authors: Kucine, Nicole, Marubayashi, Sachie, Bhagwat, Neha, Papalexi, Efthymia, Koppikar, Priya, Sanchez Martin, Marta, Dong, Lauren, Tallman, Marty S., Paietta, Elisabeth, Wang, Kai, He, Jie, Lipson, Doron, Stephens, Phil, Miller, Vince, Rowe, Jacob M., Teruya-Feldstein, Julie, Mullighan, Charles G., Ferrando, Adolfo A., Krivtsov, Andrei, Armstrong, Scott, Leung, Laura, Ochiana, Stefan O., Chiosis, Gabriela, Levine, Ross L., Kleppe, Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.11.2015; American Society of Hematology
• Subjects: Animals; Benzodioxoles - pharmacology; Brief Report; Female; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Lymphoid Neoplasia; Male; Mice; Mutation; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Purines - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-03-635821

The development of the dual Janus kinase 1/2 (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 clinicopathological 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 using 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. •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.