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

  • Authors:
    • Jihyun Park
    • Hyejoo Park
    • Ja Min Byun
    • Junshik Hong
    • Dong-Yeop Shin
    • Youngil Koh
    • Sung-Soo Yoon
  • View Affiliations

  • Published online on: August 20, 2021     https://doi.org/10.3892/ol.2021.13006
  • Article Number: 745
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Abstract

Alterations in RAS oncogenes 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.
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November-2021
Volume 22 Issue 5

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Spandidos Publications style
Park J, Park H, Byun J, Hong J, Shin D, Koh Y and Yoon S: Pan‑RAF inhibitor LY3009120 is highly synergistic with low‑dose cytarabine, but not azacitidine, in acute myeloid leukemia with <em>RAS</em> mutations. Oncol Lett 22: 745, 2021
APA
Park, J., Park, H., Byun, J., Hong, J., Shin, D., Koh, Y., & Yoon, S. (2021). Pan‑RAF inhibitor LY3009120 is highly synergistic with low‑dose cytarabine, but not azacitidine, in acute myeloid leukemia with <em>RAS</em> mutations. Oncology Letters, 22, 745. https://doi.org/10.3892/ol.2021.13006
MLA
Park, J., Park, H., Byun, J., Hong, J., Shin, D., Koh, Y., Yoon, S."Pan‑RAF inhibitor LY3009120 is highly synergistic with low‑dose cytarabine, but not azacitidine, in acute myeloid leukemia with <em>RAS</em> mutations". Oncology Letters 22.5 (2021): 745.
Chicago
Park, J., Park, H., Byun, J., Hong, J., Shin, D., Koh, Y., Yoon, S."Pan‑RAF inhibitor LY3009120 is highly synergistic with low‑dose cytarabine, but not azacitidine, in acute myeloid leukemia with <em>RAS</em> mutations". Oncology Letters 22, no. 5 (2021): 745. https://doi.org/10.3892/ol.2021.13006