Real-time fluorescent resonance energy transfer analysis to monitor drug resistance in chronic myelogenous leukemia.
Despite the initial effectiveness of oncogene-directed cancer therapeutics, acquired drug resistance remains the ultimate "Achilles' heel" for long-term durable remission in cancer patients. Acquisition of drug resistance is not more evident elsewhere than in the use of tyrosine kinase inhibitors, imatinib and dasatinib, for patients with chronic myelogenous leukemia. Hence, even though imatinib initially produces remission in the chronic phase, ultimately these therapeutics fail via the emergence of drug resistance, in which chronic myelogenous leukemia could inevitably progress to a terminal blast phase culminating in fatal outcome. Technically, it is challenging to predict the onset of drug resistance in a small number of oncogene-transformed cells, making the decision of when and how to employ second-generation tyrosine kinase inhibitors, or employ novel compounds that would be of benefit in treating drug-resistant Bcr-Abl mutants mainly retrospective. Here, we characterize a rapid and sensitive real-time fluorescent resonance energy transfer-based assay that is able to detect the in vivo activity of Bcr-Abl and its inhibition by small molecule compounds. Due to its real-time and in vivo nature, such an approach has the potential to monitor a drug-resistant phenotype, as well as to identify pharmaceutical agents that inhibit drug-resistant Bcr-Abl oncoproteins in vivo.
Tunceroglu
Ahmet
A
University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue MSB-E650, Newark, NJ 07103, USA. tuncerah@umdnj.edu
Matsuda
Michiyuki
M
Birge
Raymond B
RB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D015374:Biosensing Techniques / Q000379:methods; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003199:Computer Systems; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D008954:Models, Biological; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D013844:Thiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000069439:Dasatinib
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