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

Abstract

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.

• Authors: Nicole Kucine, Sachie Marubayashi, Neha Bhagwat, Efthymia Papalexi, Priya Koppikar, Marta Sanchez Martin, Lauren Dong, Marty S Tallman, Elisabeth Paietta, Kai Wang, Jie He, Doron Lipson, Phil Stephens, Vince Miller, Jacob M Rowe, Julie Teruya-Feldstein, Charles G Mullighan, Adolfo A Ferrando, Andrei Krivtsov, Scott Armstrong, Laura Leung, Stefan O Ochiana, Gabriela Chiosis, Ross L Levine, Maria Kleppe
• Journal: Blood (Blood) Vol. 126 Issue 22 Pg. 2479-83 (Nov 26 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26443624 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Benzodioxoles
• HSP90 Heat-Shock Proteins
• Neoplasm Proteins
• Purines
• 9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-
• JAK1 protein, human
• JAK2 protein, human
• Janus Kinase 1
• Janus Kinase 2

Topics

• Animals
• Benzodioxoles (pharmacology)
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Janus Kinase 1 (genetics, metabolism)
• Janus Kinase 2 (genetics, metabolism)
• Male
• Mice
• Mutation
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, pathology)
• Purines (pharmacology)
• Xenograft Model Antitumor Assays