Pan RAF inhibitor LY3009120 is highly synergistic with low dose cytarabine, but not azacitidine, in acute myeloid leukemia with RAS mutations
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ONCOLOGY LETTERS 22: 745, 2021
Pan‑RAF inhibitor LY3009120 is highly synergistic
with low‑dose cytarabine, but not azacitidine, in
acute myeloid leukemia with RAS mutations
JIHYUN PARK1,2, HYEJOO PARK1,2, JA MIN BYUN3, JUNSHIK HONG1‑3,
DONG‑YEOP SHIN2,3, YOUNGIL KOH1‑3 and SUNG‑SOO YOON1‑3
1
Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080;
2
Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082;
3
Department of Internal Medicine, Division of Hematology and Medical Oncology,
Seoul National University Hospital, Seoul 03080, Republic of Korea
Received April 15, 2021; Accepted July 26, 2021
DOI: 10.3892/ol.2021.13006
Abstract. Alterations in RAS oncogenes have been implicated Introduction
in various types of cancer, including acute myeloid leukemia
(AML). Considering that currently, there are no targeted Acute myeloid leukemia (AML) is a genetically heterogeneous
therapies for patients with RAS‑mutated AML despite the and highly aggressive hematological malignancy with an
poor outcomes, RAF may be a potential target for AML. In average onset age of 67 years (1). Patients with AML harbor
this study, we first analyzed the efficacy of different MAPK distinct genetic and molecular abnormalities caused by various
inhibitors in AML cell lines. We found that LY3009120, chromosomal aberrations in about 50‑60% of de novo AML
a pan‑RAF inhibitor, significantly decreased cell survival cases and 80‑95% of secondary cases (2). Classically, mutated
in RAS‑mutated AML cell lines. We then investigated the genes in AML are classified according to their characteristics,
synergistic effects of LY3009120 with either cytarabine and the gene group that affects cell proliferation includes KIT,
or azacitidine. We found that the combination of low‑dose FLT3, and RAS (3,4). MAPK, induced Ras signaling, is a major
cytarabine and LY3009120 showed a synergistic effect in oncogenic pathway in AML.
NRAS‑mutated HL‑60 cells and KRAS‑mutated NB4 cells. Alterations in RAS are involved in the progression of various
This effect was caused by a decrease in proliferation, induc‑ cancers. Missense RAS mutations causing a gain‑of‑function
tion of apoptosis, and cell growth arrest through a decrease phenotype occur in 25% of human cancers (5) and 20‑25% of
in phosphorylated MEK and ERK along with a cytotoxic AMLs. KRAS and NRAS mutations are present in 5 and 11% of
response occurring specifically for the RAS mutation of the AMLs, respectively (6). Patients with RAS‑mutated AML have
pan‑RAF inhibitor LY3009120. In addition, we confirmed shorter overall survival and AML‑free survival, higher median
that combination treatment with low‑dose cytarabine and age, and lower complete remission rates (7). In addition,
LY3009120 led to an increase in apoptosis in primary AML abnormalities in Ras proteins that regulate various functions,
cells. Our findings indicate that combination therapy with including growth, migration, adhesion, survival, and differen‑
pan‑RAF inhibitor LY3009120 and low‑dose cytarabine tiation in normal cells, affect leukemia primarily and result in
may be a promising treatment strategy for RAS‑mutated secondary effects such as chemotherapy resistance and cancer
AML. recurrence (8‑11). Therefore, the RAS status of a patient has
prognostic value and is a potent cancer biomarker (12‑15).
However, it has been challenging to target Ras directly. While
drugs targeting the downstream signaling pathway, including
RAF, mitogen‑activated protein kinase/ERK (extracellular
signal‑regulated kinase) kinase (MEK), are being developed
Correspondence to: Professor Sung‑Soo Yoon or Professor
mainly for solid tumors (12,16‑19), none of them are proven
Youngil Koh, Department of Internal Medicine, Division of
Hematology and Medical Oncology, Seoul National University
successful (20‑22). Developed as a pan‑RAF inhibitor of RAF,
Hospital, 101 Daehak‑ro, Jongno, Seoul 03080, Republic of Korea downstream of Ras, LY3009120 inhibits the activity of all
E‑mail: ssysmc@snu.ac.kr RAF isoforms (A‑RAF, B‑RAF, and c‑RAF) and RAF dimers,
E‑mail: snuhgo01@snu.ac.kr and it is currently in the first phase of clinical trials for solid
tumors (23).
Key words: acute myeloid leukemia, RAS, mitogen‑activated Therefore, in this study, using RAS mutant AML cells,
protein kinase, cytarabine, combined therapy we investigated the synergistic effects of MAPK inhibitors in
combination with low‑dose cytarabine or azacytidine, currently
used as first‑line treatments for AML in elderly patients.2 PARK et al: INHIBITION OF THE MAPK PATHWAY IN RAS MUTANT AML
Materials and methods HRP‑conjugated secondary antibody for 1 h at 37˚C. GAPDH
was used as a control marker in all the blots.
Cell culture and treatment. The three AML cell lines (HL‑60,
NB4, and KG‑1) used in the study were obtained from the Cell cycle analysis. To investigate the cell cycle profiles of the
American Type Culture Collection (ATCC) and the German treated and untreated cells after the treatment, the cells were
Collection of Microorganisms and Cell Cultures GmbH collected, washed with DPBS, and fixed with 70% ethanol. The
(DSMZ). KG‑1 and HL‑60 cell lines were authenticated fixed cells were treated with 0.4 mg/ml RNase (Promega) and
using the AmpFISTR® Identifiler ® PCR Amplification Kit 5 µl of 50 µg/ml propidium iodide (Invitrogen) (25). The stained
and the NB4 cell line using the PowerPlex®21 System Kit. cells were analyzed using FACSCanto II (BD Biosciences) and
Cells were cultured in RPMI‑1640 medium supplemented the apoptotic cells were detected using flow cytometry. For
with 10% heat‑inactivated fetal bovine serum (Gibco) and cell cycle analysis, flow cytometry data was analyzed using
1% penicillin/streptomycin (Gibco) and incubated overnight ‘ModFit’ software. Each experiment was repeated three times.
at 37˚C in 5% CO2. Cells were seeded for 24 h and treated with
cytarabine, azacytidine, LY3009120, LXH254, dabrafenib, Apoptosis assay. Apoptosis induction after single or combined treat‑
and trametinib. For single treatment, each inhibitor was treated ment with cytarabine and LY3009120 was measured using the Dead
at indicated concentrations ranging from 0.001 to 10 µM for Cell Apoptosis Kit with Annexin V/FITC and PI (Thermo Fisher
72 h. After that, the combined treatment was treated with Scientific), and DMSO was used as a control. Cells were collected
cytarabine 50 nM or/and LY3009120 6/50 nM concentration 24 or 72 h after their respective treatment and stained with
for 72 h. Each experiment was repeated five times. Annexin V/PI dye (26). Each experiment was repeated three times.
Patient samples. Bone marrow mononuclear cells (MNCs) Statistical analysis. Statistical significance among the groups
from patients with AML were isolated using the Ficoll gradient was determined using GraphPad Prism version 5.0 (GraphPad
method and cryopreserved in Cell banker 2, a serum‑free Software Inc.). Statistical analyses for the efficacy of the
medium. The MNCs of the patients were thawed at 37˚C in drugs were performed using the two‑tailed unpaired Student's
Iscove's modified Dulbecco's media containing 10% fetal t‑test. One‑way ANOVA followed by Dunnett's post hoc test
bovine serum and incubated for 24 h. were used for multiple comparisons. Combination index (CI)
values were calculated using the Chou‑Talalay equation (27).
Agents and antibodies. Cytarabine (Cytosar‑U®, Ara‑C, CI values were used to validate combinatorial effects between
Arabinosylcytosine); the pan‑RAF inhibitors, LY3009120 the two drugs; CI>1.00 indicates antagonism, CI=1.00 indicates
and LXH254; the B‑RAF inhibitor, dabrafenib; and the MEK additivity, and CIONCOLOGY LETTERS 22: 745, 2021 3 Figure 1. Effect of cytarabine and MAPK inhibitors on the proliferation of AML cells with wild‑type (KG‑1) or mutated RAS (HL‑60 and NB4). To confirm the individual effect of (A) cytarabine, (B) azacitidine, (C) LY3009120, (D) LXH254, (E) dabrafenib and (F) trametinib on AML cell lines, the cells were treated with each inhibitor at the indicated concentrations ranging from 0.001 to 10 µM for 72 h, and cell proliferation assays were performed. Following treatment with 0.1 µM LY3009120 and LXH254, HL‑60 and NB4 cells showed significantly lower cell proliferation compared to that in KG‑1 cells. ****P
4 PARK et al: INHIBITION OF THE MAPK PATHWAY IN RAS MUTANT AML
Table I. Evaluation of the synergistic effect of low‑dose cyta‑ showed a slight increase in the percentage G0G1 phase cells
rabine and LY3009120. and decrease in the S phase cells after combined treatment for
24 h (Fig. 3A) (*PONCOLOGY LETTERS 22: 745, 2021 5 Figure 2. Inhibition of the MAPK pathway protein in RAS mutant cells following combined treatment with LY3009120 and low‑dose cytarabine. (A) NRAS‑mutated HL‑60 and KRAS‑mutated NB4 cells were treated with cytarabine and/or LY3009120 for 24 h, and the levels of the MAPK pathway mole‑ cules, including p‑c‑RAF, c‑RAF, B‑RAF, p‑MEK1/2, MEK1/2, p‑ERK1/2 and ERK1/2, were analyzed via western blotting. The HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM cytarabine + 6 nM LY3009120. The NB4 cell line was treated with 50 nM cytarabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120. (B) Semi‑quantification of protein phosphorylation in HL‑60 and NB4 cells. *P
6 PARK et al: INHIBITION OF THE MAPK PATHWAY IN RAS MUTANT AML Figure 3. Cell cycle arrest of RAS mutant acute myeloid leukemia cells following combined treatment for 24 h. (A) Cells were treated with drugs alone or in combination for 24 h. The cell cycle profiles of HL‑60 and NB4 cells were analyzed using PI staining and flow cytometry. The HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM cytarabine + 6 nM LY3009120. The NB4 cell line was treated with 50 nM cytarabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120. (B) The changes in the number of cells in different phases of the cell cycle were statistically analyzed for both HL‑60 and NB4 cells. *P
ONCOLOGY LETTERS 22: 745, 2021 7 Figure 4. Cell cycle arrest of RAS mutant acute myeloid leukemia cells following combined treatment for 72 h. (A and B) Cells were treated with the indicated doses for 72 h. Cell cycle profiles of HL‑60 and NB4 were analyzed by flow cytometry and changes in the number of cells in different phases of the cell cycle were statistically analyzed for both HL‑60 and NB4 cells. The HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM cytarabine + 6 nM LY3009120. The NB4 cell line was treated with 50 nM cytarabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120. *P
8 PARK et al: INHIBITION OF THE MAPK PATHWAY IN RAS MUTANT AML Figure 5. Induction of apoptosis in RAS mutant acute myeloid leukemia cells by low dose cytarabine combined with LY3009120. Cells were treated with the inhibitors at the indicated concentrations, and the apoptotic cells were analyzed by Annexin V and PI staining. (A) HL‑60 and NB4 cells treated for 24 h. (B) HL‑60 and NB4 cells treated for 72 h. The HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM cytarabine + 6 nM LY3009120. The NB4 cell line was treated with 50 nM cytarabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120. ****P
ONCOLOGY LETTERS 22: 745, 2021 9
Figure 6. Identification of apoptosis pathway after treatment of RAS mutant acute myeloid leukemia cells with low‑dose cytarabine combined with LY3009120.
Cells were treated with the inhibitors at the indicated concentrations for 72 h to ensure cell death. Western blotting was performed using antibodies against
caspase‑3, caspase‑9 and PARP. The HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM cytarabine + 6 nM LY3009120. The NB4
cell line was treated with 50 nM cytarabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120.
could be attributed to the mechanism of action of these inhibi‑
tors.
Although synergistic effects were observed in both the
AML cell lines studied, the effects were prominent in the
NRAS‑mutated HL‑60 cells, compared to KRAS‑mutated
NB4 cells. Therefore, we further investigated the response
of the two cell lines to the RAF inhibitor LY3009120. In
HL‑60 cells, the expression of phosphorylated ERK decreased
in the LY3009120‑treated cells compared to the control cells.
Conversely, in NB4 cells, the expression of phosphorylated
ERK and phosphorylated c‑RAF increased after LY3009120
treatment. Such paradoxical activity of ERK owing to a RAF
inhibitor is well known (35‑37). Therefore, we suggest that these
paradoxical activities of LY3009120 are reflected in the differ‑
ences observed in the response of HL‑60 and NB4 cells to the
Figure 7. Induction of apoptosis in primary cells of RAS mutant AML by low‑dose combination therapy.
cytarabine combined with LY3009120. Cells were treated for 72 h to ensure Despite this complex physiological phenomenon, our
apoptosis. The apoptotic cells were analyzed by Annexin V and PI staining. The immunoblotting data show that the combination of cytarabine
HL‑60 cell line was treated with 50 nM cytarabine, 6 nM LY3009120 or 50 nM
and LY3009120 has shown synergy in RAS mutant AML,
cytarabine + 6 nM LY3009120. The NB4 cell line was treated with 50 nM cyta‑
rabine, 50 nM LY3009120 or 50 nM cytarabine + 50 nM LY3009120. *P10 PARK et al: INHIBITION OF THE MAPK PATHWAY IN RAS MUTANT AML
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