Acute Myeloid Leukemia Research Today is a free monthly online journal that collates and summarizes the latest research about Acute Myeloid Leukemia, including details on aml, symptoms, treatment, information. | ||||||||
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Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia (AML) by mutation of Asn-676 in the FLT3 tyrosine kinase domain.Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede HM, Brandts C, Serve H, Roesel J, Giles F, Feldman E, Ehninger G, Schiller GJ, Nimer S, Stone RM, Wang Y, Kindler T, Cohen PS, Huber C, Fischer T 3 Medical Department, Johannes-Gutenberg University, Mainz, Germany. Activating mutations in the FLT3 receptor tyrosine kinase (TK) occur in approximately 35% of AML patients. Therefore, targeting mutated FLT3 by tyrosine kinase inhibitors (TKI) is an attractive therapeutic strategy. Currently, several FLT3 TKI are being tested in early clinical trials. As a proof of principle, these studies showed that inhibition of FLT3 TK activity may result in measurable clinical responses. Most of these responses are transient, however, in a subset of patients blast recurrence is preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is currently unclear but is of major significance for the development of future therapeutic strategies. We performed a search for potential mechanisms of resistance in a total of 6 AML patients relapsing upon various intervals of PKC412 treatment. In an index AML patient, an algorithm of various analyses was applied using clinical material: In vivo and in vitro investigation of primary blasts at the timepoint of relapse revealed persisting TK phosphorylation of FLT3 despite sufficient serum levels of PKC412. Through additional molecular analyses of clinical samples we identified a single amino acid substitution at position 676 (N676K) within the N-lobe of the FLT3 as the sole cause of clinical resistance to PKC412 in this patient. Screening of FLT3 sequence in additional 5 AML patients relapsing upon PKC412 treatment was negative for a mutation at amino acid position 676. Reconstitution experiments expressing the N676K mutant in 32D cells demonstrated that FLT3-ITD-N676K was sufficient to confer intermediate level of resistance to PKC412 in vitro. These studies point out that a genetically complex malignancy as AML may retain dependency on a single oncogenic signal. Published 9 September 2005 in Blood.
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