RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/
MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of
acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using
LY3009120 in AML cells harboring mutations upstream and downstream of RAF.
LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse
protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/
cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably,
LY3009120 potentiated the effect of
Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of
LY3009120 and
sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using
LY3009120 results in anti-leukemic activity, and combination with
Ara-C or
sorafenib potentiates its effect.