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Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Cools, Jan Mentens, Nicole Furet, Pascal Fabbro, Doriano Clark, Jennifer J. Griffin, James D. Marynen, Peter Gilliland, Dwight Gary |
| Copyright Year | 2004 |
| Abstract | Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AML patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/64/18/6385.full.pdf |
| PubMed reference number | 15374944v1 |
| Volume Number | 64 |
| Issue Number | 18 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acute leukemia Animal Model Apoptosis FLT3 protein, human FLT3 wt Allele K 252a Mutation Myeloid Leukemia Myeloproliferative disease PKC412 Patients Precursor Cell Lymphoblastic Leukemia Lymphoma Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Small Molecule |
| Content Type | Text |
| Resource Type | Article |
