The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia.
Alessandro Di TullioKevin Rouault-PierreAnder AbarrategiSyed MianWilliam GreyJohn GribbenAengus StewartElizabeth BlackwoodDominique BonnetPublished in: Nature communications (2017)
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.
Keyphrases
- acute myeloid leukemia
- dna damage response
- dna repair
- allogeneic hematopoietic stem cell transplantation
- induced apoptosis
- healthcare
- cell cycle arrest
- dna damage
- endothelial cells
- high dose
- oxidative stress
- primary care
- cell death
- minimally invasive
- risk assessment
- emergency department
- cell proliferation
- peripheral blood
- signaling pathway
- low dose
- drug induced
- replacement therapy
- endoplasmic reticulum stress
- induced pluripotent stem cells