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Blood, 23 April 2009, Vol. 113, No. 17, pp. 3889-3890.
Fathoming Flt3OHIO STATE UNIVERSITY
Mutated Flt3 has emerged as a promising drug target in AML. In this issue of Blood, Breitenbuecher and colleagues describe a common novel type of Flt3 ITD mutations and, in 2 additional studies, Breitenbuecher and colleagues as well as Zhou and colleagues present mechanisms for resistance to Flt3 kinase inhibitors.
Two principal types of Flt3 mutations have been described in AML. The first is an internal tandem duplication (ITD) in the intracellular domain of the receptor found in about 20% to 30% of AML patients.1,2 The second, point mutations predominantly substitutions of aspartate at position 835, are located in the activation loop of the kinase domain and is present in about 10% of patients.3,4 In the first paper by Breitenbuecher et al, the authors perform a systematic analysis of the ITD insertion sites in 753 AML cases positive for Flt3 ITD.5 To date, all ITDs have been localized to the juxtamembrane region of Flt3, which is encoded by exon 14. Interestingly, the authors find ITD insertions not only in the juxtamembrane region but also in the adjacent first kinase domain, which is encoded by exon 15. In total, 28.7% of ITDs were nontypical ITDs. The authors subsequently use one of the identified nontypical ITD mutations (Flt3 ITD627E) to study its biological activity. The mutated receptor demonstrated ligand independent autophosphorylation reflecting constitutive activation. Furthermore, Flt3 ITD627E was able to transform hematopoietic 32D cells, and it caused a fatal myeloproliferative disease in a mouse model. Therefore, the nontraditional insertion mutations appear to contribute to AML oncogenesis and constitute promising drug targets. In their second paper, Breitenbuecher et al explore why the AML patient, in whom the Flt3 ITD627E was discovered, showed upfront resistance to PKC412. PKC412 is one of the Flt3 kinase inhibitors currently in clinical trials.6 The authors show that the resistance was due to enhanced association of Grb2 with Flt3 ITD627E. As a result, the antiapoptotic Mcl-1 protein was significantly up-regulated. Down-regulation of Mcl-1 by RNA interference resensitized cells to PKC412. In their paper, Zhou et al also investigate resistance mechanisms vis-à-vis Flt3 inhibitors.7 The authors generate an AML cell line that was resistant to the Flt3 inhibitor ABT-869 by culturing the cells with the compound for an extended period of time. The basis for resistance was the up-regulation of Flt3 Ligand expression. This promoted the activation of STAT1, STAT3, and STAT5 and an increase in the antiapoptotic protein survivin. Cells could be resensitized to ABT-869 by down-regulation of survivin and by inhibiting STAT signaling with a small molecule named IDR E804. Today, there are multiple Flt3 inhibitors in clinical trials.8 The most advanced compound is PKC412 which is currently being tested in a phase 3 trial in AML patients with mutated Flt3. Clinical results with various compounds have been mixed so far. Although there are significant responses in some patients, in many other patients, there are no responses or the responses are limited and short-lived. Are the disappointing results due to the fact that the Flt3 kinase inhibitors we are testing in patients are suboptimal compounds? Or does the underlying biology of AML provide common preexisting or easily acquired resistance mechanisms that blunt the effect of inhibiting mutated Flt3? The studies presented in this issue of Blood reaffirm that mutated Flt3 is an exciting drug target in AML. But the studies also suggest a careful exploration of why patients fail Flt3 inhibitor therapy. Based on the identified resistance mechanisms, we may be able to devise alternative or complementary therapeutic approaches that fully exploit the promise of mutated Flt3 as a drug target in AML.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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