The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia
journal contributionposted on 12.08.2020, 11:42 authored by Alessandro Di Tullio, Kevin Rouault-Pierre, Ander Abarrategi, Syed Mian, William Grey, John Gribben, Aengus Stewart, Elizabeth Blackwood, Dominique Bonnet
Cytarabine (AraC) represents the most effective single agent treatment for AML. Nevertheless, overriding AraC resistance in AML remains an unmet medical need. Here we show that the CHK1 inhibitor (CHK1i) GDC-0575 enhances AraC-mediated killing of AML cells both in vitro and in vivo, thus abrogating any potential chemoresistance mechanisms involving DNA repair. Importantly, this combination of drugs does not affect normal long-term hematopoietic stem/progenitors. Moreover, the addition of CHK1i to AraC does not generate de novo mutations and in patients' samples where AraC is mutagenic, addition of CHK1i appears to eliminate the generation of mutant clones. Finally, we observe that persistent residual leukemic cells are quiescent and can become responsive to the treatment when forced into cycle via granulocyte colony-stimulating factor (G-CSF) administration. This drug combination (AraC+CHK1i+G-CSF) will open the doors for a more efficient treatment of AML in the clinic.
AnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorCheckpoint Kinase 1CytarabineDrug Resistance, NeoplasmFemaleGranulocyte Colony-Stimulating FactorHL-60 CellsHematopoiesisHumansLeukemia, Myeloid, AcuteMaleMiceMice, Inbred NODMice, SCIDMutationPiperidinesProtein Kinase InhibitorsPyridinesPyrrolesU937 CellsXenograft Model Antitumor AssaysBonnet FC001045CBBRF-ackFC-ackLM-ackAS-ackHP-ack