Venetoclax synergizes with Wnt/β-catenin inhibitor C-82 in acute myeloid leukemia by increasing the degradation of Mcl-1 protein

  • Cancer Cell Int. 2025 May 29;25(1):197. doi: 10.1186/s12935-025-03825-8.
Mengya Pan  #  1 ,  Changqing Jiao  #  1 ,  Menghua Sun  #  1 ,  Duo Jin  1 ,  Yin Wang  1 ,  Haoxuan Wu  1 ,  Yan Zhang  1 ,  Enbo Chen  1 ,  Bobin Su  1 ,  Junjie Zhou  2 ,  Xiaoying Liu  3  4 ,  Jian Ge  5  6  7
Affiliations
  • 1. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University Institute of Hematology, Hefei, 230022, China.
  • 2. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University Institute of Hematology, Hefei, 230022, China. [email protected].
  • 3. School of Life Sciences, Anhui Medical University, Hefei, 230032, China. [email protected].
  • 4. Henan International Joint Laboratory of Non-Coding RNA and Metabolism in Cancer, Henan Provincial Key Laboratory of Long Non-Coding RNA and Cancer Metabolism, Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Zhengzhou, 450053, China. [email protected].
  • 5. Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University Institute of Hematology, Hefei, 230022, China. [email protected].
  • 6. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China. [email protected].
  • 7. Anhui Provincial Institute of Translational Medicine, Hefei, 230032, China. [email protected].
  • # Contributed equally.
PMID: 40442688 DOI: 10.1186/s12935-025-03825-8
Abstract

Background: Due to compensatory survival signalling and overexpression of anti-apoptotic Bcl-2 Family proteins, the majority of AML patients developed acquired resistance of venetoclax (VEN) to combination therapy of VEN with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs). Dysregulation of the Wnt/β-catenin signalling pathway is intently associated with leukemia development and chemotherapy resistance. However, there is currently no Wnt/β-catenin Inhibitor approved for clinical use and it is not clear whether targeting the Wnt/β-catenin pathway enhances the anti-leukemic activity of VEN.

Methods: Analysis of the AML patient's data in the BeatAML and GEO databases. Establishing the MOLM13 venetoclax-resistant cell line (MOLM13-R cells) based on the MOLM13 parental cell line. CCK-8, Annexin-V/PI and Western blotting were performed to assess the effects of the combination of Wnt/β-catenin Inhibitor C-82 and VEN in AML cell lines. The potential mechanisms of synergistic effects of the two-drug combination were explored by Western blotting and ubiquitination immunoprecipitation.

Results: We displayed that the expression of β-catenin abnormally upregulated in AML patients and MOLM13-R cells. Knockdown of β-catenin could increase cell Apoptosis in MOLM13-R cells. Combined treatment of C-82 with VEN synergistically inhibited AML cell growth and increased Apoptosis. Mechanistically, C-82 disrupted the stability of Mcl-1 protein, and Mcl-1 downregulation was associated with different phosphorylation sites of Mcl-1 and proteasomal degradation. The combination of C-82 and VEN synergistically induced concurrent mitochondrial-associated Apoptosis and gasdermin E (GSDME)-dependent Pyroptosis.

Conclusion: Our findings propose an effective treatment strategy for AML patients through the combination of C-82 and VEN, positioning this regimen as a promising therapeutic option.

Keywords
Acute myeloid leukemia; Drug resistance; Mcl-1; Venetoclax; Wnt/β-catenin.
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