ena-STUDY-Francis Crick Institute-24-10-2017-16:34:55:352-226
The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human Acute Myeloid Leukemia while sparing normal hematopoiesis
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-mediatedkilling of AML cells both in vitro and in vivo, thus abrogating any potential chemo-resistance 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 (Ara.C+ CHHK1i + G-CSF) will open the doors for a more efficient treatment of AML in the clinic.
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-mediatedkilling of AML cells both in vitro and in vivo, thus abrogating any potential chemo-resistance 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 (Ara.C+ CHHK1i + G-CSF) will open the doors for a more efficient treatment of AML in the clinic.