A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia.

摘要: Some tumors are dependent on the continued activity of a single oncogene for maintenance their malignant phenotype. The best-studied example is Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although clinical success Abl kinase inhibitor imatinib against chronic-phase CML emphasizes importance developing therapeutic strategies aimed at this target, resistance to poses major problem ultimate therapy by agent. We hypothesized sequential blockade strategy that designed decrease expression protein, with goal complementing action activity. In study, flavopiridol, an transcription, homoharringtonine (HHT), synthesis inhibitor, and were used singly combination Bcr-Abl-positive human cell line K562. Flavopiridol alone inhibited phosphorylation RNA polymerase II COOH-terminal domain, specifically reduced II-directed mRNA synthesis, decreased transcript levels. HHT level. Imatinib directly Bcr-Abl. combinations flavopiridol synergistically clonogenicity as evaluated median-effect method. Greater synergy was observed when given sequentially compared simultaneous administration. Imatinib-resistant Ba/F3 cells transfected express E255K T315I mutations not cross-resistant HHT. These results provided rationale inhibitors transcription and/or translation specific inhibitors.