title: Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways.
abstract: Continuous treatment of malignancies with tyrosine kinase inhibitors (TKIs) may select for resistant clones (ie, imatinib mesylate). To study resistance to TKIs targeting FLT3, a receptor tyrosine kinase that is frequently mutated in acute myelogenous leukemia (AML), we developed resistant human cell lines through prolonged coculture with FLT3 TKIs. FLT3 TKI-resistant cell lines and primary samples still exhibit inhibition of FLT3 phosphorylation on FLT3 TKI treatment. However, FLT3 TKI-resistant cell lines and primary samples often show continued activation of downstream PI3K/Akt and/or Ras/MEK/MAPK signaling pathways as well as continued expression of genes involved in FLT3-mediated cellular transformation. Inhibition of these signaling pathways restores partial sensitivity to FLT3 TKIs. Mutational screening of FLT3 TKI-resistant cell lines revealed activating N-Ras mutations in 2 cell lines that were not present in the parental FLT3 TKI-sensitive cell line. Taken together, these data indicate that FLT3 TKI-resistant cells most frequently become FLT3 independent because of activation of parallel signaling pathways that provide compensatory survival/proliferation signals when FLT3 is inhibited. Anti-FLT3 mAb treatment was still cytotoxic to FLT3 TKI-resistant clones. An approach combining FLT3 TKIs with anti-FLT3 antibodies and/or inhibitors of important pathways downstream of FLT3 may reduce the chances of developing resistance.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Obdulio
authors.initials: O
authors.lastname: Piloto
authors.forename: Melissa
authors.initials: M
authors.lastname: Wright
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Kim
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.forename: Donald
authors.initials: D
authors.lastname: Small
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins