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Ref Type Journal Article
PMID (29162833)
Authors Di Tullio A, Rouault-Pierre K, Abarrategi A, Mian S, Grey W, Gribben J, Stewart A, Blackwood E, Bonnet D
Title The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia.
Journal Nature communications
Vol 8
Issue 1
Date 2017 Nov 22
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
GDC-0575 GDC-0575 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
GDC-0575 ARRY-575|RG7741 CHK1 Inhibitor 14 GDC-0575 selectively inhibits CHK1, which potentially results in increased response to chemotherapeutic agents (PMID: 29162833).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown acute myeloid leukemia not applicable Cytarabine + GDC-0575 Preclinical - Pdx & cell culture Actionable In a preclinical study, combination of GDC-0575 and Cytosar-U (cytarabine) resulted in enhanced killing of acute myeloid leukemia cells in both cell line and patient-derived xenograft models (PMID: 29162833). 29162833
Unknown unknown acute myeloid leukemia not applicable Cytarabine + Filgrastim + GDC-0575 Preclinical - Pdx Actionable In a preclinical study, addition of Neupogen (filgrastim) to the combination of GDC-0575 and Cytosar-U (cytarabine) resulted in enhanced killing of acute myeloid leukemia cells in patient-derived xenograft (PDX) models (PMID: 29162833). 29162833