title: Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: delineation of anti-leukemic mechanisms of action.
abstract: Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit "off-target" effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti-leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects.
authors.affiliation: INSERM, U848, 94805 Villejuif, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Lainey
authors.forename: Sylvain
authors.initials: S
authors.lastname: Thépot
authors.forename: Cyrielle
authors.initials: C
authors.lastname: Bouteloup
authors.forename: Marie
authors.initials: M
authors.lastname: Sébert
authors.forename: Lionel
authors.initials: L
authors.lastname: Adès
authors.forename: Maximilien
authors.initials: M
authors.lastname: Tailler
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases