Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways.

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Abstract Text:

Obdulio Piloto,Melissa Wright,Patrick Brown,Kyu-Tae Kim,Mark Levis,Donald Small,

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.

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Publishing Authors By Initials

O Piloto,M Wright,P Brown,KT Kim,M Levis,D Small,

For similar enzymes and coenzymes: enzymes: hydrolases: acid anhydride hydrolases: gtp phosphohydrolases: gtp-binding proteins: monomeric gtp-binding proteins: ras proteins research abstracts see: enzymes and coenzymes: enzymes: hydrolases: acid anhydride hydrolases: gtp phosphohydrolases: gtp-binding proteins: monomeric gtp-binding proteins: ras proteins research

PUBMED ID PMID:

MEDLINE DATE:

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Blood

VOLUME: 109

Page Numbers: 1643-52

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 17

MONTH: 10

YEAR: 2006

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7603509

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Keywords Mesh Terms:

KEYWORDS: ras Proteins

MESH TERMS: genetics

Chemical & Substance for Abstract: Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Information

Substance Name: ras Proteins

Registry Number: EC 3.6.5.2

Grant and Affiliation Information for Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways.

AFFILIATION: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA95600-03

ACRONYM: CA

MEDLINETA: Blood

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways Related Publications

• 281.
• Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone.
• Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study.
• An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.
• Blank augmentation protocol for improving the robustness of multivariate calibrations.
• CA3 NMDA receptors are required for experience-dependent shifts in hippocampal activity.
• Cognitive deficits in preclinical Alzheimer's disease and vascular dementia: patterns of findings from the Kungsholmen Project.
• Constitutive Fms-like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells.
• Globally distributed mycobacterial fish pathogens produce a novel plasmid-encoded toxic macrolide, mycolactone F.
• Hearing lips and seeing voices: how cortical areas supporting speech production mediate audiovisual speech perception.
• Imaging the earliest stages of Alzheimer's disease.
• Imaging-guided microarray: isolating molecular profiles that dissociate Alzheimer's disease from normal aging.
• Jagged-1hi or Delta-1hi thymic stromal cell populations can trigger acquisition of Thy-1 and loss of B220.
• Longitudinal mapping of mouse cerebral blood volume with MRI.
• Molecular evolution of the Li/li chemical defence polymorphism in white clover (Trifolium repens L.).
• Photoacoustic characterization of protein dynamics following CO photodetachment from fully reduced bovine cytochrome c oxidase.
• Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.
• Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways.
• Psychosocial functioning of adults who experienced substance use disorders as adolescents.
• Quantitative determination of ethanol in heated plumes by passive Fourier transform infrared remote sensing measurements.
• Repetition suppression for spoken sentences and the effect of task demands.
• Screening for depressive symptoms in patients with unresectable lung cancer.
• Selective expression of an aP2/Fatty Acid Binding Protein 4-Cre transgene in non-adipogenic tissues during embryonic development.
• Spectral simulation methodology for calibration transfer of near-infrared spectra.
• Speech-associated gestures, Broca's area, and the human mirror system.
• Task-dependent changes in brain activation following therapy for nonfluent aphasia: discussion of two individual cases.
• The mind of expert motor performance is cool and focused.
• Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease.
• Trying to detect taste in a tasteless solution: modulation of early gustatory cortex by attention to taste.
• Using the COPE intervention for family caregivers to improve symptoms of hospice homecare patients: a clinical trial.