Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Drug Resistance, Neoplasm/drug effects , Harringtonines/therapeutic use , Leukemia, Myeloid, Accelerated Phase/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Antineoplastic Agents, Phytogenic/pharmacology , Drug Resistance, Neoplasm/physiology , Follow-Up Studies , Harringtonines/pharmacology , Homoharringtonine , Humans , Leukemia, Myeloid, Accelerated Phase/enzymology , Leukemia, Myeloid, Accelerated Phase/mortality , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Survival Rate/trendsABSTRACT
The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.
Subject(s)
Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , K562 Cells/drug effects , Leukemia, Myeloid, Accelerated Phase/enzymology , Neoplasm Proteins/antagonists & inhibitors , Nitriles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinolines/pharmacology , Aniline Compounds/chemistry , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Dasatinib , Drug Delivery Systems , Drug Screening Assays, Antitumor , Fusion Proteins, bcr-abl/antagonists & inhibitors , Gene Expression Profiling , Humans , K562 Cells/enzymology , Leukemia, Myeloid, Accelerated Phase/pathology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/enzymology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Nitriles/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Pyrimidines/pharmacology , Quinolines/chemistry , Signal Transduction/drug effects , Substrate Specificity , Thiazoles/pharmacology , src-Family Kinases/antagonists & inhibitorsABSTRACT
Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective BCR-ABL tyrosine kinase inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2-611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at www.clinicaltrials.gov as NCT00384228.
