Pan-RAF inhibitor LY3009120 is highly synergistic with low-dose cytarabine, but not azacitidine, in acute myeloid leukemia with RAS mutations

摘要

Alterations inRASoncogenes have been implicated in various types of cancer, including acute myeloid leukemia (AML). Considering that currently, there are no targeted therapies for patients with RAS-mutated AML despite the poor outcomes, RAF may be a potential target for AML. In this study, we first analyzed the efficacy of different MAPK inhibitors in AML cell lines. We found that LY3009120, a pan-RAF inhibitor, significantly decreased cell survival in RAS-mutated AML cell lines. We then investigated the synergistic effects of LY3009120 with either cytarabine or azacitidine. We found that the combination of low-dose cytarabine and LY3009120 showed a synergistic effect in NRAS-mutated HL-60 cells and KRAS-mutated NB4 cells. This effect was caused by a decrease in proliferation, induction of apoptosis, and cell growth arrest through a decrease in phosphorylated MEK and ERK along with a cytotoxic response occurring specifically for the RAS mutation of the pan-RAF inhibitor LY3009120. In addition, we confirmed that combination treatment with low-dose cytarabine and LY3009120 led to an increase in apoptosis in primary AML cells. Our findings indicate that combination therapy with pan-RAF inhibitor LY3009120 and low-dose cytarabine may be a promising treatment strategy for RAS-mutated AML.