title: A sequential blockade strategy for the design of combination therapies to overcome oncogene addiction in chronic myelogenous leukemia.
abstract: Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronic-phase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors.
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D004357:Drug Synergism; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006248:Harringtonines / Q000008:administration & dosage / Q000494:pharmacology; D000077863:Homoharringtonine; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D001549:Benzamides; D005419:Flavonoids; D006248:Harringtonines; D010879:Piperazines; D010880:Piperidines; D011743:Pyrimidines; D012334:RNA, Neoplasm; C077990:alvocidib; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl