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.
- 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