1. Academic Validation
  2. Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines

Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines

  • Cell Oncol (Dordr). 2022 Aug 29. doi: 10.1007/s13402-022-00703-7.
Sen Zhang  # 1 Jun Liu  # 1 Zi-Yi Lu  # 1 Yu-Tong Xue 1 Xing-Ru Mu 1 Yang Liu 1 2 Jiang Cao 2 Zhen-Yu Li 2 Feng Li 3 Kai-Lin Xu 4 5 Qing-Yun Wu 6 7
Affiliations

Affiliations

  • 1 Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3 Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, 221002, People's Republic of China. lifeng1982315@163.com.
  • 4 Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. lihmd@163.com.
  • 5 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. lihmd@163.com.
  • 6 Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. qywu82@163.com.
  • 7 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. qywu82@163.com.
  • # Contributed equally.
Abstract

Purpose: FLT3 mutations occurred in approximately one third of patients with acute myeloid leukemia (AML). FLT3-ITD mutations caused the constitutive activation of the Ras/MAPK signaling pathway. Ribosomal S6 Kinases (RSKs) were serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. However, roles and mechanisms of RSKs inhibitor LJH-685, and combinational effects of LJH-685 and FLT3 Inhibitor FF-10101 on AML cells were till unclear.

Methods: Cell viability assay, CFSE assay, RT-qPCR, Colony formation assay, PI stain, Annexin-V/7-AAD double stain, Western blot, and Xenogeneic transplantation methods were used to used to investigate roles and mechanisms of LJH-685 in the leukemogenesis of AML.

Results: LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the Apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the Apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations. Moreover, in vivo experiments also indicated that LJH-685 combined with FF-10101 or Daunorubicin prolonged the survival time of NSG mice and reduced the leukemogenesis of AML.

Conclusion: Thus, these observations demonstrated combination of RSK inhibitor LJH-685 and FLT3 Inhibitor FF-10101 showed synergism anti-leukemia effects in AML cell lines with FLT3-ITD mutations via inhibiting MAPK-RSKs-YB-1 pathway and provided new targets for therapeutic intervention especially for AML with FLT3-ITD mutations and Daunorubicin-resistant AML.

Keywords

AML; FF-10101; FLT3-ITD; LJH-685; Proliferation; RSKs.

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