Proteasome inhibition in chronic myeloid leukaemia

RC0254 Neoplasms. Tumors. Oncology (including Cancer);RM Therapeutics. Pharmacology

Heaney, Nicholas Benjamin ; Holyoake, Tessa

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: chronic myeloid leukaemia, proteasome inhibitor, tyrosine kinase inhibitor, stem cell;   

Others  :  http://theses.gla.ac.uk/832/1/2009heaneymd.pdf

来源: University of Glasgow

【 摘 要 】

CML is treated effectively with TKI, however two key problems remain - the insensitivity of CM HSC to TKI and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and PI are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in CD34+ cells taken at diagnosis from patients with CP CML cells, with an LD50 below concentrations achieved in vivo. We also demonstrate for the first time that CD34+38- CML cells, representing the TKI-insensitive primitive HSC, are similarly susceptible. Bortezomib is associated with inhibition of proteasome activity, however that of BCR-ABL appears unaffected. Significant synergy is seen when bortezomib and dasatinib are used in combination. We also demonstrate that bortezomib is effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. Therefore we believe that bortezomib offers a potential therapeutic option in CML by targeting both TKI-insensitive stem cells and TKI-resistant BCR-ABL mutations.