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The Hsp90 inhibitor SNX-7081 synergizes with and restores sensitivity to fludarabine in chronic lymphocytic leukemia cells with lesions in the TP53 pathway: a potential treatment strategy for fludarabine refractory disease.

Abstract
Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.
AuthorsO Giles Best, Yiping Che, Nisha Singh, Cecily Forsyth, Richard I Christopherson, Stephen P Mulligan
JournalLeukemia & lymphoma (Leuk Lymphoma) Vol. 53 Issue 7 Pg. 1367-75 (Jul 2012) ISSN: 1029-2403 [Electronic] United States
PMID22149137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzamides
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HSP90 Heat-Shock Proteins
  • SNX-7081
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • Vidarabine
  • fludarabine
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Ataxia Telangiectasia Mutated Proteins
  • Benzamides (pharmacology)
  • Cell Cycle (drug effects)
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • DNA-Binding Proteins (genetics, metabolism)
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm (drug effects)
  • Drug Synergism
  • Flow Cytometry
  • HL-60 Cells
  • HSP90 Heat-Shock Proteins (antagonists & inhibitors)
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism, pathology)
  • Mutation
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Signal Transduction (drug effects)
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 (genetics, metabolism)
  • Tumor Suppressor Proteins (genetics, metabolism)
  • Vidarabine (analogs & derivatives, pharmacology)

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