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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
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Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias

Nicole Kucine1, Sachie Marubayashi2, Neha Bhagwat3

  • 1Human 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;

Blood
|October 8, 2015
PubMed

Insights

Heat shock protein 90 (HSP90) inhibition shows promise for treating Janus kinase (JAK)-mutated acute lymphoblastic leukemia (ALL). This approach may overcome resistance to existing JAK-inhibitor therapies in ALL.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Myeloproliferative neoplasms (MPNs) are treated with Janus kinase 1/2 (JAK1/2) inhibitors like ruxolitinib.
  • Ruxolitinib is being investigated for JAK-mutated acute lymphoblastic leukemia (ALL).
  • Limited responses to JAK inhibition in MPNs highlight the need for novel therapies targeting JAK kinase-dependent malignancies.

Purpose of the Study:

  • To evaluate the efficacy of heat shock protein 90 (HSP90) inhibition as a therapeutic strategy for JAK-dependent ALL.
  • To determine if HSP90 inhibition can overcome resistance to JAK-inhibitor therapy in ALL cells.

Main Methods:

  • Utilized a purine-scaffold HSP90 inhibitor in early clinical development.
  • Tested the therapeutic approach in JAK-dependent ALL models.
  • Assessed the ability of HSP90 inhibition to overcome JAK-inhibitor persistence in ALL cells.

Main Results:

  • HSP90 inhibition demonstrated effectiveness in treating JAK-dependent ALL.
  • This therapeutic strategy successfully overcame persistence to JAK-inhibitor therapy in ALL cells.

Conclusions:

  • HSP90 inhibition represents a viable therapeutic approach for JAK-dependent ALL.
  • Targeting HSP90 offers a potential strategy to overcome resistance to JAK inhibitors in ALL.

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