The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29162833.
- Also identified by DOI 10.1038/s41467-017-01834-4 and PMC identifier 5698422.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Checkpoint Kinase 1
- Cytarabine
- Granulocyte Colony-Stimulating Factor
- Leukemia, Myeloid, Acute
- Piperidines
- Protein Kinase Inhibitors
- Pyridines
- Pyrroles