title: 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.
authors.affiliation: Northern Blood Research Centre, Kolling Institute, Royal North Shore Hospital, Sydney, Australia. gilesbest@yahoo.com
authors.forename: O Giles
authors.initials: OG
authors.lastname: Best
authors.forename: Yiping
authors.initials: Y
authors.lastname: Che
authors.forename: Nisha
authors.initials: N
authors.lastname: Singh
authors.forename: Cecily
authors.initials: C
authors.lastname: Forsyth
authors.forename: Richard I
authors.initials: RI
authors.lastname: Christopherson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Mulligan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; C535175:SNX-7081; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D014740:Vidarabine; C024352:fludarabine