A Possible New Solution to Chronic Myeloid Leukemia

            Imatinib is an inhibitor that binds to the inactive form of BCR-ABL tyrosine kinase. When the activation loop of the kinase is closed, then the imatinib inhibitor binds to it and therefore does not allow adenosine triphosphate to bind in its binding site. By inhibiting the bind site, ATP cannot attach to the BCR-ABL kinase domain and phosphorylate it. Without phosphorylation of the domain it cannot be activated and therefore will not multiply the tumor cell.

            Imatinib has been used a therapy for patients with chronic myeloid leukemia for several years now. However due to point mutations in the BCR-ABL kinase domain, resistance to imatinib has been occurring even after treatment has taken place in these patients. Scientists began to study this phenomenon at a deeper perspective to understand why this happening.

            The SRC is another domain that has about the same confirmation as the ABL, but imatinib does not bind to it. However there are other molecules that do inhibit SCR that could eventually be used against the imatinib resistance. There are 17 known mutations in the BCR-ABL kinase domain that have been proved to be in correlation to imatinib resistance. These point mutations are specific regions of amino acids, which inhibit kinase from binding to them by changing the specific confirmation that it needs.

            This is where the other molecules that bind to SCR could come into play and aid in not allowing that happen. BMS-354825 is a known inhibitor of the SRC kinase and it was tested to see if it would inhibit BCR-ABL the same way and it turned out that it actually did inhibit it. Not only did it inhibit the nonmutated BCR-ABL, but most of the imatinib-resistance BCR-ABL isoforms as well. The only once that was not inhibited was the mutant T315I. There were mutations that were more sensitive than others, and therefore requirement much less. The levels of sensibility were correlated to the levels of imatinib resistance, and could potentially provide insight to how much is needed for therapeutic treatments.

            To study these levels even deeper, mice with different isoforms of BCR-ABL were used and treated with BMS-354825. It started off that the untreated mice had obvious signs of disease through bioluminescence imaging. Both nonmutant and isoform mice were vehicle-treated, meaning they were given the negative control, and others were given the dose of BMS-354825. The results were that the vehicle treated mice still had the prolonged disease. In contrast, the mice that were BMS-354825-treated and had the specific M351T mutant were healthy with lower signs of disease through bioluminescence imaging. In addition to that the mice with T315I mutant did not respond to the BMS-354825 treatment.

This was further tested through in vitro colony-forming-unit assays, to see how it effective it would be on humans. It was founded that BMS-354825 did not inhibit the growth of bone marrow from healthy people, but it did inhibit the ones from chronic myeloid leukemia patients.

            The experiment design of testing both nonmutated and isoforms of mice was designed well and executed effectively. Although the mutant M351T accounts for 15 to 20% of chronic myeloid leukemia patients, and the other mutations as well. This therapy potentially does bring a new way of addressing the disease, especially with patients with the mutant M351T, but there is still more testing to be done on the other mutants. The mutant T315I needs more investigation as to why it is resistant and other methods need to be found to address that one specifically. The other mutations that were not referred to also need to be investigated furthermore. The conclusions made were not valid for the same reason that the other mutants were not accounted for anywhere in the article. 

Resource

  Shah, Neil P, et al. “Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor.” 2004.