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Blood. 2015 Nov 26;126(22):2479-83. doi: 10.1182/blood-2015-03-635821. Epub 2015 Oct 6.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pediatrics, Division of Hematology/Oncology, Weill Cornell Medical College, New York, NY;
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Gerstner Sloan Kettering Graduate School in Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY;
4
Institute for Cancer Genetics, Columbia University, New York, NY;
5
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY;
6
Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY;
7
Foundation Medicine, Cambridge, MA;
8
Department of Hematology and Bone Marrow Transplantation, The Rambam Medical Center, Haifa, Israel;
9
Department of Pathology, Icahn School of Medicine, Mount Sinai, New York, NY;
10
Department of Pathology and Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN; and.
11
Cancer Biology and Genetics Program, Center for Epigenetics Research, and.
12
Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY.
13
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY; Center for Epigenetics Research, and.

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.

PMID:
26443624
PMCID:
PMC4661170
DOI:
10.1182/blood-2015-03-635821
[Indexed for MEDLINE]
Free PMC Article

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