title: Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment.
abstract: Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.
authors.affiliation: Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Oaxaca
authors.affiliation: Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Yang-Reid
authors.affiliation: Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
authors.forename: Georgialina
authors.initials: G
authors.lastname: Rodriguez
authors.affiliation: Department of Mathematical Sciences and Border Biomedical Research Center, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA.
authors.forename: Joan G
authors.initials: JG
authors.lastname: Staniswalis
authors.affiliation: Department of Biological Sciences, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX, 79968, USA. rkirken@utep.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kirken
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D005576:Colforsin; C545373:ponatinib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases
keywords: BCR-ABL; Chronic myeloid leukemia; Forskolin; Imatinib; Ponatinib; Tyrosine kinase inhibitor