The success of the kinase inhibitor Gleevec in the treatment of chronic myelogenous leukaemia — which is caused by the aberrant activity of the BCR–ABL tyrosine kinase — has given much encouragement for the development of other molecularly targeted therapies. As two reports in Cancer Cell now indicate, inhibitors of the FLT3 kinase, which is mutated in ∼30% of patients with acute myelogenous leukaemia (AML), could be promising candidates for targeted treatment of this disease.
The first study involved the kinase inhibitor CT53518, which is selective for FLT3 and two other kinases, platelet-derived-growth-factor receptor (PDGFR) and KIT, in vitro. CT53518 was found to inhibit several different constitutively active FLT3 mutants that were cloned from patients with AML and expressed in Ba/F3 cells, and also to induce apoptotic cell death in human AML cell lines with mutations in FLT3. Encouraged by these observations, Kelly et al. tested CT53518 in vivo in two mouse models of mutant-FLT3-mediated AML, and found that CT53518 resulted in a significant decrease in disease progression, as assessed by spleen weight and white blood cell (WBC) count, and an increase in survival. Furthermore, CT53518 was shown to have suitable pharmacokinetic and toxicity profiles for clinical use.
The second study, by Weisberg et al., assessed the activity of the kinase inhibitor PKC412 — which targets FLT3, and also the kinases KDR, PDGFR, KIT and protein kinase C — and found it to be highly toxic to Ba/F3 cells that expressed mutant FLT3 receptors from AML patients. And in a mouse model of mutant-FLT3-mediated leukaemia, PKC412 treatment completely blocked the development of leukaemia, whereas all of the mice in the placebo group developed fatal disease. Moreover, spleen weights and WBC counts were also significantly lower in the treated mice.
Both of these studies strongly support the idea that FLT3 is potentially a good drug target in AML. PKC412 and CT53518 are now being evaluated in clinical trials for AML, and it seems likely that several other FLT3 inhibitors will also be clinically tested. It will be of considerable interest to compare their efficacies and toxicities, as these are likely to be influenced by the non-FLT3 targets of each drug, which might differ significantly.
References
ORIGINAL RESEARCH PAPERS
Kelly, L. M. et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia. Cancer Cell 1, 421–432 (2002)
Weisberg, E. et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small-molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1, 433–443 (2002)
FURTHER READING
Capdeville, R. et al. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493–502 (2002)
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Kirkpatrick, P. Next in line?. Nat Rev Cancer 2, 556 (2002). https://doi.org/10.1038/nrc880
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DOI: https://doi.org/10.1038/nrc880